{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:16:48Z","timestamp":1790810208090,"version":"4.1.0"},"reference-count":69,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T00:00:00Z","timestamp":1674086400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T00:00:00Z","timestamp":1674086400000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T00:00:00Z","timestamp":1674086400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015539","name":"Australian Government","doi-asserted-by":"publisher","award":["Research Training Program Scholarship"],"award-info":[{"award-number":["Research Training Program Scholarship"]}],"id":[{"id":"10.13039\/100015539","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001773","name":"University of New South Wales","doi-asserted-by":"publisher","award":["Scientia PhD Scholarship"],"award-info":[{"award-number":["Scientia PhD Scholarship"]}],"id":[{"id":"10.13039\/501100001773","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001104","name":"RANZCOG Research Foundation","doi-asserted-by":"publisher","award":["Mary Elizabeth Courier Research Scholarship"],"award-info":[{"award-number":["Mary Elizabeth Courier Research Scholarship"]}],"id":[{"id":"10.13039\/501100001104","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001171","name":"Cancer Institute NSW","doi-asserted-by":"publisher","award":["Career Development Fellowship"],"award-info":[{"award-number":["Career Development Fellowship"]}],"id":[{"id":"10.13039\/501100001171","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000923","name":"Australian Research Council","doi-asserted-by":"publisher","award":["Grant DP170101178"],"award-info":[{"award-number":["Grant DP170101178"]}],"id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009287","name":"NSW Health","doi-asserted-by":"publisher","award":["Investigator Development Grant"],"award-info":[{"award-number":["Investigator Development Grant"]}],"id":[{"id":"10.13039\/501100009287","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001171","name":"Cancer Institute NSW","doi-asserted-by":"publisher","award":["2021\/CDF1120"],"award-info":[{"award-number":["2021\/CDF1120"]}],"id":[{"id":"10.13039\/501100001171","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2022,12,13]]},"abstract":"<jats:p>Cholesterol synthesis is both energy- and oxygen-intensive, yet relatively little is known of the regulatory effects of hypoxia on pathway enzymes. We previously showed that the rate-limiting and first oxygen-dependent enzyme of the committed cholesterol synthesis pathway, squalene monooxygenase (SM), can undergo partial proteasomal degradation that renders it constitutively active. Here, we show hypoxia is a physiological trigger for this truncation, which occurs through a two-part mechanism: (1) increased targeting of SM to the proteasome via stabilization of the E3 ubiquitin ligase MARCHF6 and (2) accumulation of the SM substrate, squalene, which impedes the complete degradation of SM and liberates its truncated form. This preserves SM activity and downstream pathway flux during hypoxia. These results uncover a feedforward mechanism that allows SM to accommodate fluctuating substrate levels and may contribute to its widely reported oncogenic properties.<\/jats:p>","DOI":"10.7554\/elife.82843","type":"journal-article","created":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T09:15:12Z","timestamp":1670922912000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.82843","source":"Crossref","is-referenced-by-count":19,"title":["Hypoxia truncates and constitutively activates the key cholesterol synthesis enzyme squalene monooxygenase"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6506-5249","authenticated-orcid":true,"given":"Hudson W","family":"Coates","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03r8z3t63","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biotechnology and Biomolecular Sciences, UNSW Sydney","place":["Sydney, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle M","family":"Capell-Hattam","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03r8z3t63","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biotechnology and Biomolecular Sciences, UNSW Sydney","place":["Sydney, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen M","family":"Olzomer","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03r8z3t63","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biotechnology and Biomolecular Sciences, UNSW Sydney","place":["Sydney, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6648-017X","authenticated-orcid":true,"given":"Ximing","family":"Du","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03r8z3t63","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biotechnology and Biomolecular Sciences, UNSW Sydney","place":["Sydney, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhonda","family":"Farrell","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/022arq532","id-type":"ROR","asserted-by":"publisher"}],"name":"Prince of Wales Private Hospital","place":["Randwick, Australia"]},{"id":[{"id":"https:\/\/ror.org\/00qeks103","id-type":"ROR","asserted-by":"publisher"}],"name":"Chris O\u2019Brien Lifehouse","place":["Camperdown, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8482-6031","authenticated-orcid":true,"given":"Hongyuan","family":"Yang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03r8z3t63","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biotechnology and Biomolecular Sciences, UNSW Sydney","place":["Sydney, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances L","family":"Byrne","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03r8z3t63","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biotechnology and Biomolecular Sciences, UNSW Sydney","place":["Sydney, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4475-0116","authenticated-orcid":true,"given":"Andrew J","family":"Brown","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03r8z3t63","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biotechnology and Biomolecular Sciences, UNSW Sydney","place":["Sydney, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2023,1,19]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.bbrc.2006.11.014","article-title":"Site-Directed mutagenesis of conserved aromatic residues in rat squalene epoxidase","volume":"352","author":"Abe","year":"2007","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/s0006-291x(05)90003-x","article-title":"Epoxidation of 2,3-oxidosqualene to 2,3;22,23-squalene dioxide by squalene epoxidase","volume":"185","author":"Bai","year":"1992","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"bib3","doi-asserted-by":"publisher","DOI":"10.1186\/s12944-021-01476-y","article-title":"Identification of prognostic lipid droplet-associated genes in pancreatic cancer patients via bioinformatics analysis","volume":"20","author":"Bai","year":"2021","journal-title":"Lipids in Health and Disease"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"1670","DOI":"10.1016\/S0140-6736(10)61350-5","article-title":"Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials","volume":"376","author":"Baigent","year":"2010","journal-title":"Lancet"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"7929","DOI":"10.1096\/fj.201802650RR","article-title":"Primary endothelial cell-specific regulation of hypoxia-inducible factor (HIF) -1 and HIF-2 and their target gene expression profiles during hypoxia","volume":"33","author":"Bartoszewski","year":"2019","journal-title":"FASEB Journal"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"2570","DOI":"10.1128\/MCB.00166-09","article-title":"Hypoxia-Induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains","volume":"29","author":"Bellot","year":"2009","journal-title":"Molecular and Cellular Biology"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"Journal of the Royal Statistical Society"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"3470","DOI":"10.1038\/sj.emboj.7600777","article-title":"Er stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth","volume":"24","author":"Bi","year":"2005","journal-title":"The EMBO Journal"},{"key":"bib9","doi-asserted-by":"publisher","DOI":"10.1038\/srep19435","article-title":"Squalene epoxidase is a bona fide oncogene by amplification with clinical relevance in breast cancer","volume":"6","author":"Brown","year":"2016","journal-title":"Scientific Reports"},{"key":"bib10","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/B978-0-12-824048-9.00005-5","volume-title":"In Biochemistry of Lipids, Lipoproteins and Membranes","author":"Brown","year":"2021"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1159\/000366348","article-title":"Hypoxia induces dysregulation of lipid metabolism in HepG2 cells via activation of HIF-2\u03b1","volume":"34","author":"Cao","year":"2014","journal-title":"Cellular Physiology and Biochemistry"},{"key":"bib12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jlr.2022.100295","article-title":"The non catalytic protein ERG28 has a functional role in cholesterol synthesis and is coregulated transcriptionally","volume":"63","author":"Capell-Hattam","year":"2022","journal-title":"Journal of Lipid Research"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"19959","DOI":"10.1074\/jbc.M117.794230","article-title":"A conserved degron containing an amphipathic helix regulates the cholesterol-mediated turnover of human squalene monooxygenase, a rate-limiting enzyme in cholesterol synthesis","volume":"292","author":"Chua","year":"2017","journal-title":"The Journal of Biological Chemistry"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"8134","DOI":"10.1074\/jbc.RA119.007798","article-title":"Non-Canonical ubiquitination of the cholesterol-regulated degron of squalene monooxygenase","volume":"294","author":"Chua","year":"2019","journal-title":"The Journal of Biological Chemistry"},{"key":"bib15","doi-asserted-by":"publisher","DOI":"10.1016\/j.plipres.2020.101033","article-title":"Squalene monooxygenase: a journey to the heart of cholesterol synthesis","volume":"79","author":"Chua","year":"2020","journal-title":"Progress in Lipid Research"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"1656","DOI":"10.1016\/j.bbalip.2019.08.006","article-title":"Consulting prostate cancer cohort data uncovers transcriptional control: regulation of the MARCH6 gene","volume":"1864","author":"Coates","year":"2019","journal-title":"Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids"},{"key":"bib17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100731","article-title":"The mammalian cholesterol synthesis enzyme squalene monooxygenase is proteasomally truncated to a constitutively active form","volume":"296","author":"Coates","year":"2021","journal-title":"The Journal of Biological Chemistry"},{"key":"bib18","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.46490","article-title":"Lack of activity of recombinant HIF prolyl hydroxylases (PHDs) on reported non-HIF substrates","volume":"8","author":"Cockman","year":"2019","journal-title":"eLife"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1002\/jcp.21584","article-title":"Activation of HIF-1alpha in exponentially growing cells via hypoxic stimulation is independent of the Akt\/mTOR pathway","volume":"218","author":"Dayan","year":"2009","journal-title":"Journal of Cellular Physiology"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.bbrc.2006.12.159","article-title":"Transcriptional downregulation of sterol metabolism genes in murine liver exposed to acute hypobaric hypoxia","volume":"354","author":"Dolt","year":"2007","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"bib21","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.00953","article-title":"Sterol homeostasis requires regulated degradation of squalene monooxygenase by the ubiquitin ligase Doa10\/Teb4","volume":"2","author":"Foresti","year":"2013","journal-title":"eLife"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/j.cmet.2011.01.015","article-title":"Cholesterol-dependent degradation of squalene monooxygenase, a control point in cholesterol synthesis beyond HMG-coa reductase","volume":"13","author":"Gill","year":"2011","journal-title":"Cell Metabolism"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/0076-6879(83)98152-1","article-title":"Receptor-Mediated endocytosis of low-density lipoprotein in cultured cells","volume":"98","author":"Goldstein","year":"1983","journal-title":"Methods in Enzymology"},{"key":"bib24","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0999-8","article-title":"Genomic alterations underlie a pan-cancer metabolic shift associated with tumour hypoxia","volume":"17","author":"Haider","year":"2016","journal-title":"Genome Biology"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/S0005-2728(02)00346-8","article-title":"Squalane is in the midplane of the lipid bilayer: implications for its function as a proton permeability barrier","volume":"1556","author":"Hau\u00df","year":"2002","journal-title":"Biochimica et Biophysica Acta - Bioenergetics"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1002\/cac2.12187","article-title":"Squalene epoxidase promotes colorectal cancer cell proliferation through accumulating calcitriol and activating CYP24A1-mediated MAPK signaling","volume":"41","author":"He","year":"2021","journal-title":"Cancer Communication"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"1298","DOI":"10.1158\/0008-5472.CAN-21-2229","article-title":"Targeting squalene epoxidase interrupts homologous recombination via the ER stress response and promotes radiotherapy efficacy","volume":"82","author":"Hong","year":"2022","journal-title":"Cancer Research"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"D512","DOI":"10.1093\/nar\/gku1267","article-title":"PhosphoSitePlus, 2014: mutations, ptms and recalibrations","volume":"43","author":"Hornbeck","year":"2015","journal-title":"Nucleic Acids Research"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"12027","DOI":"10.1073\/pnas.1534923100","article-title":"Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes","volume":"100","author":"Horton","year":"2003","journal-title":"PNAS"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"27533","DOI":"10.1074\/jbc.M115.675181","article-title":"The regulatory domain of squalene monooxygenase contains a re-entrant loop and senses cholesterol via a conformational change","volume":"290","author":"Howe","year":"2015","journal-title":"The Journal of Biological Chemistry"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1126\/science.1059817","article-title":"Hifalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing","volume":"292","author":"Ivan","year":"2001","journal-title":"Science"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1189\/jlb.1210683","article-title":"Toll-Like receptor activation and hypoxia use distinct signaling pathways to stabilize hypoxia-inducible factor 1\u03b1 (HIF1A) and result in differential HIF1A-dependent gene expression","volume":"90","author":"Jantsch","year":"2011","journal-title":"Journal of Leukocyte Biology"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1053\/j.gastro.2020.09.009","article-title":"Reduction of squalene epoxidase by cholesterol accumulation accelerates colorectal cancer progression and metastasis","volume":"160","author":"Jun","year":"2021","journal-title":"Gastroenterology"},{"key":"bib34","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25325-9","article-title":"MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer","volume":"12","author":"Kalogirou","year":"2021","journal-title":"Nature Communications"},{"key":"bib35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0116740","article-title":"Global profiling of metabolic adaptation to hypoxic stress in human glioblastoma cells","volume":"10","author":"Kucharzewska","year":"2015","journal-title":"PLOS ONE"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"2063","DOI":"10.1158\/0008-5472.CAN-15-2613","article-title":"The role of cholesterol in cancer","volume":"76","author":"Kuzu","year":"2016","journal-title":"Cancer Research"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"W171","DOI":"10.1093\/nar\/gkz365","article-title":"CHOPCHOP V3: expanding the CRISPR web toolbox beyond genome editing","volume":"47","author":"Labun","year":"2019","journal-title":"Nucleic Acids Research"},{"key":"bib38","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/S0022-2275(20)37014-0","article-title":"Measurement of squalene in human tissues and plasma: validation and application","volume":"17","author":"Liu","year":"1976","journal-title":"Journal of Lipid Research"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/j.molcel.2006.01.010","article-title":"Hypoxia-Induced energy stress regulates mRNA translation and cell growth","volume":"21","author":"Liu","year":"2006","journal-title":"Molecular Cell"},{"key":"bib40","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aap9840","article-title":"Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target","volume":"10","author":"Liu","year":"2018","journal-title":"Science Translational Medicine"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"2467","DOI":"10.1053\/j.gastro.2021.02.051","article-title":"Squalene epoxidase induces nonalcoholic steatohepatitis via binding to carbonic anhydrase III and is a therapeutic target","volume":"160","author":"Liu","year":"2021","journal-title":"Gastroenterology"},{"key":"bib42","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07959-4","article-title":"A chemical biology screen identifies A vulnerability of neuroendocrine cancer cells to SQLE inhibition","volume":"10","author":"Mahoney","year":"2019","journal-title":"Nature Communications"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1097\/MOL.0b013e32836484a4","article-title":"Hypoxia in atherosclerosis and inflammation","volume":"24","author":"Marsch","year":"2013","journal-title":"Current Opinion in Lipidology"},{"key":"bib44","doi-asserted-by":"publisher","DOI":"10.1259\/bjr.20130676","article-title":"Defining normoxia, physoxia and hypoxia in tumours-implications for treatment response","volume":"87","author":"McKeown","year":"2014","journal-title":"The British Journal of Radiology"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1016\/S0022-2275(20)38144-X","article-title":"Diurnal variation of cholesterol precursors squalene and methyl sterols in human plasma lipoproteins","volume":"23","author":"Miettinen","year":"1982","journal-title":"Journal of Lipid Research"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1161\/01.atv.10.1.106","article-title":"Effects of hypoxia on sterol synthesis, acyl-coa: cholesterol acyltransferase activity, and efflux of cholesterol in cultured rabbit skin fibroblasts","volume":"10","author":"Mukodani","year":"1990","journal-title":"Arteriosclerosis"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"27436","DOI":"10.1074\/jbc.M704976200","article-title":"Hypoxia stimulates degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase through accumulation of lanosterol and hypoxia-inducible factor-mediated induction of insigs","volume":"282","author":"Nguyen","year":"2007","journal-title":"The Journal of Biological Chemistry"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1038\/s41556-022-00973-1","article-title":"The MARCHF6 E3 ubiquitin ligase acts as an NADPH sensor for the regulation of ferroptosis","volume":"24","author":"Nguyen","year":"2022","journal-title":"Nature Cell Biology"},{"key":"bib49","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07928-x","article-title":"Structure and inhibition mechanism of the catalytic domain of human squalene epoxidase","volume":"10","author":"Padyana","year":"2019","journal-title":"Nature Communications"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1161\/CIRCRESAHA.111.246363","article-title":"Hypoxia is present in murine atherosclerotic plaques and has multiple adverse effects on macrophage lipid metabolism","volume":"109","author":"Parathath","year":"2011","journal-title":"Circulation Research"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1194\/jlr.R009548","article-title":"Malformation syndromes caused by disorders of cholesterol synthesis","volume":"52","author":"Porter","year":"2011","journal-title":"Journal of Lipid Research"},{"key":"bib52","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2020.613162","article-title":"Gene expression changes and associated pathways involved in the progression of prostate cancer advanced stages","volume":"11","author":"Pudova","year":"2020","journal-title":"Frontiers in Genetics"},{"key":"bib53","doi-asserted-by":"publisher","first-page":"2281","DOI":"10.1038\/nprot.2013.143","article-title":"Genome engineering using the CRISPR-Cas9 system","volume":"8","author":"Ran","year":"2013","journal-title":"Nature Protocols"},{"key":"bib54","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1126\/science.aaf4405","article-title":"Hypoxic control of metastasis","volume":"352","author":"Rankin","year":"2016","journal-title":"Science"},{"key":"bib55","doi-asserted-by":"publisher","first-page":"4430","DOI":"10.1158\/0008-5472.CAN-16-0530","article-title":"Phgdh expression is required for mitochondrial redox homeostasis, breast cancer stem cell maintenance, and lung metastasis","volume":"76","author":"Samanta","year":"2016","journal-title":"Cancer Research"},{"key":"bib56","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C (T) method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nature Protocols"},{"key":"bib57","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1042\/BCJ20190647","article-title":"The cholesterol synthesis enzyme lanosterol 14\u03b1-demethylase is post-translationally regulated by the E3 ubiquitin ligase MARCH6","volume":"477","author":"Scott","year":"2020","journal-title":"The Biochemical Journal"},{"key":"bib58","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1158\/1541-7786.MCR-13-0607","article-title":"Hifs enhance the transcriptional activation and splicing of adrenomedullin","volume":"12","author":"Sena","year":"2014","journal-title":"Molecular Cancer Research"},{"key":"bib59","doi-asserted-by":"publisher","first-page":"2436","DOI":"10.1074\/jbc.RA118.005069","article-title":"Cholesterol increases protein levels of the E3 ligase MARCH6 and thereby stimulates protein degradation","volume":"294","author":"Sharpe","year":"2019","journal-title":"The Journal of Biological Chemistry"},{"key":"bib60","doi-asserted-by":"publisher","first-page":"7624","DOI":"10.1038\/sj.onc.1204972","article-title":"Cell density mediated pericellular hypoxia leads to induction of HIF-1alpha via nitric oxide and Ras\/MAP kinase mediated signaling pathways","volume":"20","author":"Sheta","year":"2001","journal-title":"Oncogene"},{"key":"bib61","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0083888","article-title":"A practical comparison of ligation-independent cloning techniques","volume":"8","author":"Stevenson","year":"2013","journal-title":"PLOS ONE"},{"key":"bib62","doi-asserted-by":"publisher","first-page":"4785","DOI":"10.1158\/0008-5472.CAN-16-0903","article-title":"Cholesterol metabolism and prostate cancer lethality","volume":"76","author":"Stopsack","year":"2016","journal-title":"Cancer Research"},{"key":"bib63","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/S0022-2275(20)39755-8","article-title":"Role of liver in the synthesis of cholesterol and the clearance of low density lipoproteins in the cynomolgus monkey","volume":"36","author":"Turley","year":"1995","journal-title":"Journal of Lipid Research"},{"key":"bib64","doi-asserted-by":"publisher","DOI":"10.1186\/1476-511X-6-10","article-title":"Synthesis of the oxysterol, 24 (S), 25-epoxycholesterol, parallels cholesterol production and may protect against cellular accumulation of newly-synthesized cholesterol","volume":"6","author":"Wong","year":"2007","journal-title":"Lipids in Health and Disease"},{"key":"bib65","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1074\/jbc.M706416200","article-title":"Endogenous 24 (S),25-epoxycholesterol fine-tunes acute control of cellular cholesterol homeostasis","volume":"283","author":"Wong","year":"2008","journal-title":"The Journal of Biological Chemistry"},{"key":"bib66","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18411-x","article-title":"Regulation of cellular sterol homeostasis by the oxygen responsive noncoding RNA lincnors","volume":"11","author":"Wu","year":"2020","journal-title":"Nature Communications"},{"key":"bib67","doi-asserted-by":"publisher","first-page":"7150","DOI":"10.1073\/pnas.1915923117","article-title":"A key mammalian cholesterol synthesis enzyme, squalene monooxygenase, is allosterically stabilized by its substrate","volume":"117","author":"Yoshioka","year":"2020","journal-title":"PNAS"},{"key":"bib68","doi-asserted-by":"publisher","first-page":"1262","DOI":"10.1128\/MCB.01140-13","article-title":"The E3 ubiquitin ligase MARCH6 degrades squalene monooxygenase and affects 3-hydroxy-3-methyl-glutaryl coenzyme A reductase and the cholesterol synthesis pathway","volume":"34","author":"Zelcer","year":"2014","journal-title":"Molecular and Cellular Biology"},{"key":"bib69","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1194\/jlr.M043521","article-title":"Foxo4 interacts with the sterol regulatory factor SREBP2 and the hypoxia inducible factor HIF2\u03b1 at the CYP51 promoter","volume":"55","author":"Zhu","year":"2014","journal-title":"Journal of Lipid Research"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/82843\/elife-82843-v1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/82843\/elife-82843-v1.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/82843","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T21:08:54Z","timestamp":1697058534000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/82843"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,19]]},"references-count":69,"alternative-id":["10.7554\/eLife.82843"],"URL":"https:\/\/doi.org\/10.7554\/elife.82843","archive":["CLOCKSS"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.08.18.504470","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.7554\/eLife.82843.sa2","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.82843.sa1","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.82843.sa0","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,19]]},"assertion":[{"value":"single anonymised","name":"peer_review_transparency","label":"Peer review transparency","group":{"name":"peer_review_taxonomy"}},{"value":"other reviewer(s), editor","name":"peer_review_interaction","label":"Peer review interaction","group":{"name":"peer_review_taxonomy"}},{"value":"review summaries, review reports, author\/editor communication, reviewer identities reviewer opt in, editor identities","name":"peer_review_published","label":"Peer review published","group":{"name":"peer_review_taxonomy"}},{"value":"open (sign in with ORCID iD required)","name":"post_publication_commenting","label":"Post publication commenting","group":{"name":"post_publication_commenting"}}],"article-number":"e82843"}}