{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:57:51Z","timestamp":1768870671126,"version":"3.49.0"},"reference-count":34,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,5,26]],"date-time":"2022-05-26T00:00:00Z","timestamp":1653523200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 109-2314-B-038-052-MY3"],"award-info":[{"award-number":["MOST 109-2314-B-038-052-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST108-2314-B-038-096"],"award-info":[{"award-number":["MOST108-2314-B-038-096"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST110-2314-B-038-058"],"award-info":[{"award-number":["MOST110-2314-B-038-058"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 110-2314-B-038-060"],"award-info":[{"award-number":["MOST 110-2314-B-038-060"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 109-2314-B-038-107-MY3"],"award-info":[{"award-number":["MOST 109-2314-B-038-107-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 110-2635-B-038-001"],"award-info":[{"award-number":["MOST 110-2635-B-038-001"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 110WFD2010656"],"award-info":[{"award-number":["MOST 110WFD2010656"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["109TMU-SHH-20"],"award-info":[{"award-number":["109TMU-SHH-20"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Taipei Medical University-Shuang Ho Hospital, Taiwan","award":["MOST 109-2314-B-038-052-MY3"],"award-info":[{"award-number":["MOST 109-2314-B-038-052-MY3"]}]},{"name":"Taipei Medical University-Shuang Ho Hospital, Taiwan","award":["MOST108-2314-B-038-096"],"award-info":[{"award-number":["MOST108-2314-B-038-096"]}]},{"name":"Taipei Medical University-Shuang Ho Hospital, Taiwan","award":["MOST110-2314-B-038-058"],"award-info":[{"award-number":["MOST110-2314-B-038-058"]}]},{"name":"Taipei Medical University-Shuang Ho Hospital, Taiwan","award":["MOST 110-2314-B-038-060"],"award-info":[{"award-number":["MOST 110-2314-B-038-060"]}]},{"name":"Taipei Medical University-Shuang Ho Hospital, Taiwan","award":["MOST 109-2314-B-038-107-MY3"],"award-info":[{"award-number":["MOST 109-2314-B-038-107-MY3"]}]},{"name":"Taipei Medical University-Shuang Ho Hospital, Taiwan","award":["MOST 110-2635-B-038-001"],"award-info":[{"award-number":["MOST 110-2635-B-038-001"]}]},{"name":"Taipei Medical University-Shuang Ho Hospital, Taiwan","award":["MOST 110WFD2010656"],"award-info":[{"award-number":["MOST 110WFD2010656"]}]},{"name":"Taipei Medical University-Shuang Ho Hospital, Taiwan","award":["109TMU-SHH-20"],"award-info":[{"award-number":["109TMU-SHH-20"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Adenomyosis is linked to dysmenorrhea and infertility. The pathogenesis of adenomyosis remains unclear, and little is known of the genetic and epigenetic changes in the eutopic endometrium in adenomyosis, which may predispose patients to the invasion and migration of endometrial tissues into the myometrium. Transcriptome studies have identified genes related to various cell behaviors but no targets for therapeutic intervention. The epigenetics of the eutopic endometrium in adenomyosis have rarely been investigated. Endometrial tissue was obtained from premenopausal women with (n = 32) or without adenomyosis (n = 17) who underwent hysterectomy aged 34\u201357 years at a tertiary hospital. The methylome and transcriptome were assessed by using a Methylation 450 K BeadChip array and Affymetrix expression microarray. Protein expression was examined by immunohistochemistry. Differential methylation analysis revealed 53 lowly methylated genes and 176 highly methylated genes with consistent gene expression in adenomyosis, including three genes encoding potassium ion channels. High expression of KCNK9 in the eutopic and ectopic endometria in patients with adenomyosis but not in normal controls was observed. Hormone-free, antibody-based KCNK9 targeting is a potential therapeutic strategy for adenomyosis-related dysmenorrhea, menorrhagia, and infertility.<\/jats:p>","DOI":"10.3390\/ijms23115973","type":"journal-article","created":{"date-parts":[[2022,5,26]],"date-time":"2022-05-26T08:50:22Z","timestamp":1653555022000},"page":"5973","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Epigenomic Analysis Reveals the KCNK9 Potassium Channel as a Potential Therapeutic Target for Adenomyosis"],"prefix":"10.3390","volume":"23","author":[{"given":"Ling-Hui","family":"Chu","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chi-Chun","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan"},{"name":"Nuwa Fertility Center, Taipei 106467, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Phui-Ly","family":"Liew","sequence":"additional","affiliation":[{"name":"Department of Pathology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan"},{"name":"Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chien-Wen","family":"Chen","sequence":"additional","affiliation":[{"name":"Dr Wang Reproductive Fertility Center, Taipei 110007, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1114-6382","authenticated-orcid":false,"given":"Po-Hsuan","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan"},{"name":"Translational Epigenetics Center, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kuo-Chang","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan"},{"name":"Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hung-Cheng","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan"},{"name":"Translational Epigenetics Center, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan"},{"name":"Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, National Defense Medical Center, Taipei 11490, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui-Lan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan"},{"name":"Translational Epigenetics Center, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan"},{"name":"Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4870-3664","authenticated-orcid":false,"given":"Lin-Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan"},{"name":"Translational Epigenetics Center, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.bpobgyn.2006.01.007","article-title":"History of adenomyosis","volume":"20","author":"Benagiano","year":"2006","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1093\/humupd\/dmt052","article-title":"Structural and molecular features of the endomyometrium in endometriosis and adenomyosis","volume":"20","author":"Benagiano","year":"2014","journal-title":"Hum. Reprod. Update"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1097\/OGX.0000000000000346","article-title":"The Impact of Adenomyosis on Women\u2019s Fertility","volume":"71","author":"Harada","year":"2016","journal-title":"Obstet. Gynecol. Surv."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1093\/humupd\/dmv044","article-title":"Infertility and reproductive disorders: Impact of hormonal and inflammatory mechanisms on pregnancy outcome","volume":"22","author":"Vannuccini","year":"2016","journal-title":"Hum. Reprod. Update"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.bpobgyn.2006.01.010","article-title":"Adenomyosis: The pathophysiology of an oestrogen-dependent disease","volume":"20","author":"Kitawaki","year":"2006","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.1517\/14656566.2014.953055","article-title":"An update on the pharmacological management of adenomyosis","volume":"15","author":"Streuli","year":"2014","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1016\/j.rbmo.2017.06.016","article-title":"Pathogenesis of adenomyosis: An update on molecular mechanisms","volume":"35","author":"Vannuccini","year":"2017","journal-title":"Reprod. BioMed. Online"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1177\/1933719116657192","article-title":"Expression of Inflammatory and Neurogenic Mediators in Adenomyosis","volume":"24","author":"Carrarelli","year":"2017","journal-title":"Reprod. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"150","DOI":"10.5468\/ogs.2015.58.2.150","article-title":"Innervation in women with uterine myoma and adenomyosis","volume":"58","author":"Choi","year":"2015","journal-title":"Obstet. Gynecol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.fertnstert.2012.08.038","article-title":"Dysmenorrhea and its severity are associated with increased uterine contractility and overexpression of oxytocin receptor (OTR) in women with symptomatic adenomyosis","volume":"99","author":"Guo","year":"2013","journal-title":"Fertil. Steril."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"786132","DOI":"10.1155\/2012\/786132","article-title":"Infertility and adenomyosis","volume":"2012","author":"Campo","year":"2012","journal-title":"Obstet. Gynecol. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/j.fertnstert.2010.09.060","article-title":"HOXA10 expression is decreased in endometrium of women with adenomyosis","volume":"95","author":"Fischer","year":"2011","journal-title":"Fertil. Steril."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"153","DOI":"10.3109\/01443615.2015.1036403","article-title":"A current view of the role of epigenetic changes in the aetiopathogenesis of endometriosis","volume":"36","author":"Kokcu","year":"2016","journal-title":"J. Obstet. Gynaecol. J. Inst. Obstet. Gynaecol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4003","DOI":"10.1210\/en.2009-0404","article-title":"Minireview: Epigenetic changes in ovarian cancer","volume":"150","author":"Balch","year":"2009","journal-title":"Endocrinology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"983","DOI":"10.3390\/ijms12020983","article-title":"Epigenetic regulation of cancer-associated genes in ovarian cancer","volume":"12","author":"Kwon","year":"2011","journal-title":"Int. J. Mol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1080\/19396368.2018.1563844","article-title":"Preliminary functional inquiry of lncRNA ENST00000433673 in embryo implantation using bioinformatics analysis","volume":"65","author":"Li","year":"2019","journal-title":"Syst. Biol. Reprod. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.ajhg.2011.03.003","article-title":"Tobacco-smoking-related differential DNA methylation: 27K discovery and replication","volume":"88","author":"Breitling","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1146\/annurev-nutr-121415-112634","article-title":"Diet, Nutrition, and Cancer Epigenetics","volume":"36","author":"Sapienza","year":"2016","journal-title":"Annu. Rev. Nutr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-1-4939-8751-1_1","article-title":"Early Epigenetic Markers for Precision Medicine","volume":"1856","author":"Dumitrescu","year":"2018","journal-title":"Methods Mol. Biol"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.fertnstert.2020.08.1398","article-title":"Insight into epigenetics of human endometriosis organoids: DNA methylation analysis of HOX genes and their cofactors","volume":"115","author":"Esfandiari","year":"2021","journal-title":"Fertil. Steril."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"eaaf7533","DOI":"10.1126\/scitranslmed.aaf7533","article-title":"Loss of HDAC3 results in nonreceptive endometrium and female infertility","volume":"11","author":"Kim","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"122","DOI":"10.3109\/01677063.2013.856430","article-title":"Variations in potassium channel genes are associated with breast pain in women prior to breast cancer surgery","volume":"28","author":"Langford","year":"2014","journal-title":"J. Neurogenet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/j.bcp.2015.10.017","article-title":"Inhibition of Kv channel expression by NSAIDs depolarizes membrane potential and inhibits cell migration by disrupting calpain signaling","volume":"98","author":"Silver","year":"2015","journal-title":"Biochem. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1007\/s00018-015-2076-y","article-title":"WNT-5A: Signaling and functions in health and disease","volume":"73","author":"Kumawat","year":"2016","journal-title":"Cell Mol. Life Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1097\/PAS.0b013e31822d787c","article-title":"PAX2 and PAX8 expression in primary and metastatic mullerian epithelial tumors: A comprehensive comparison","volume":"35","author":"Ozcan","year":"2011","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_26","first-page":"5478","article-title":"Role of Wnt5a in the differentiation of human embryonic stem cells into endometrium-like cells","volume":"8","author":"Yu","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1093\/molehr\/gal076","article-title":"Molecular characterization of human adenomyosis","volume":"12","author":"Hever","year":"2006","journal-title":"Mol. Hum. Reprod."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1038\/onc.2016.304","article-title":"Wnt signaling in cancer","volume":"36","author":"Zhan","year":"2017","journal-title":"Oncogene"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.retram.2016.04.008","article-title":"Down-regulation of tumor suppressor PDCD4 expression in endometrium of adenomyosis patients","volume":"64","author":"Liu","year":"2016","journal-title":"Curr. Res. Transl. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.ejogrb.2016.12.004","article-title":"Immunohistochemical expression pattern of metastasis suppressor KISS-1 protein in adenomyosis lesions and normal endometrium","volume":"210","author":"Kolioulis","year":"2017","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1111\/j.1582-4934.2012.01656.x","article-title":"A role for two-pore potassium (K2P) channels in endometrial epithelial function","volume":"17","author":"Patel","year":"2013","journal-title":"J. Cell Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"10339","DOI":"10.1038\/ncomms10339","article-title":"A monoclonal antibody against KCNK9 K(+) channel extracellular domain inhibits tumour growth and metastasis","volume":"7","author":"Sun","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1177\/1933719116650758","article-title":"Global Transcriptome Abnormalities of the Eutopic Endometrium from Women with Adenomyosis","volume":"23","author":"Herndon","year":"2016","journal-title":"Reprod. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources","volume":"4","author":"Huang","year":"2009","journal-title":"Nat. Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/11\/5973\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:18:53Z","timestamp":1760138333000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/11\/5973"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,26]]},"references-count":34,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["ijms23115973"],"URL":"https:\/\/doi.org\/10.3390\/ijms23115973","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,26]]}}}