{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T15:48:40Z","timestamp":1785599320360,"version":"3.56.0"},"reference-count":78,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T00:00:00Z","timestamp":1733097600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2024,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Solar radiation is the main source of human exposure to UV rays, which is the major carcinogen in skin cancers by inducing DNA damage. Skin cells repair these damages by activating the DNA damage response (DDR) to safeguard genome integrity, thereby preventing skin cancers. Peroxisome proliferator\u2010activated receptor beta (PPAR\u03b2), a druggable transcription factor, is involved in the development of UV\u2010dependent skin cancers, although its role is not mechanistically elucidated. We showed previously that PPAR\u03b2 knockout (KO) mice are less prone to UV\u2010induced skin cancers. Here, we report that PPAR\u03b2 directly regulates gene expression programs associated with cell cycle and DNA repair pathways in normal human epidermal keratinocytes (NHEK). The loss of function of PPAR\u03b2 in human keratinocytes led to a downregulation in the expression of key cell cycle regulators, including cyclins and cyclin\u2010dependent kinases (CDKs). Simultaneously, it upregulated the expression of p21 protein, a known CDK inhibitor. These molecular alterations resulted in a significant reduction in cell proliferation and induced cell cycle arrest at the G2\/M phase. Moreover, the absence of functional PPAR\u03b2 disrupted the expression and activation of the ataxia telangiectasia and Rad3\u2010related (ATR) pathway, a critical component of the cellular response to UV\u2010induced DNA damage. The alterations in the ATR pathway likely contributed to an increased apoptotic response of NHEK to UV radiation. Using a mouse melanoma model, we demonstrated that the depletion of PPAR\u03b2 decreases tumorigenicity of melanoma cells and delays tumor formation. Our data suggest that PPAR\u03b2 inhibition could be considered as a therapeutic target for the prevention of UV\u2010induced skin cancers, by regulating cell proliferation, attenuating DDR, and eliminating skin cells with high UV\u2010induced mutational burden.<\/jats:p>","DOI":"10.1096\/fj.202401950r","type":"journal-article","created":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T10:04:54Z","timestamp":1733133894000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Transcriptional and functional regulation of cell cycle and\u00a0\n                    <scp>UV<\/scp>\n                    response by\n                    <scp>PPAR\u03b2<\/scp>\n                    in human skin epidermal cells"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6923-8370","authenticated-orcid":false,"given":"Thanh Nhan","family":"Nguyen","sequence":"first","affiliation":[{"name":"Center for Integrative Genomics University of Lausanne  Lausanne Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carine","family":"Winkler","sequence":"additional","affiliation":[{"name":"Center for Integrative Genomics University of Lausanne  Lausanne Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Ginster","sequence":"additional","affiliation":[{"name":"Center for Integrative Genomics University of Lausanne  Lausanne Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0190-1586","authenticated-orcid":false,"given":"St\u00e9phanie","family":"Claudinot","sequence":"additional","affiliation":[{"name":"Center for Integrative Genomics University of Lausanne  Lausanne Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2963-2100","authenticated-orcid":false,"given":"Liliane","family":"Michalik","sequence":"additional","affiliation":[{"name":"Center for Integrative Genomics University of Lausanne  Lausanne Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1656-9480","authenticated-orcid":false,"given":"Paris","family":"Jafari","sequence":"additional","affiliation":[{"name":"Center for Integrative Genomics University of Lausanne  Lausanne Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,12,2]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-4632.2010.04474.x"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410873200"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0110-x"},{"issue":"3","key":"e_1_2_11_5_1","first-page":"243","article-title":"The intersection between DNA damage response and cell death pathways","volume":"34","author":"Nowsheen S","year":"2012","journal-title":"Exp Oncol"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.261271.115"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2015.2"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08467"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2076"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27057-2"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21249715"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21062061"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.207501"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(02)00646-9"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00436-07"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200809028"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M412829200"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201302666"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgn278"},{"issue":"4","key":"e_1_2_11_20_1","article-title":"Ultraviolet radiation and chronic inflammation\u2010molecules and mechanisms involved in skin carcinogenesis: a narrative review","volume":"11","author":"Ciazynska M","year":"2021","journal-title":"Life (Basel)"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201505384"},{"issue":"1","key":"e_1_2_11_22_1","first-page":"4","article-title":"Production and titration of lentiviral vectors","volume":"53","author":"Salmon P","year":"2006","journal-title":"Curr Protoc Neurosci"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.949802"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M210511200"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2016.27"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4504"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-022-00988-z"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21197264"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2010.6"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3546"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/php.13245"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/35044005"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0707579104"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(03)00110-7"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku501"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23137058"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2657"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2003.08.001"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.027730"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2008.435"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/php.13164"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(03)00207-5"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2007-0190"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1155\/2008\/614852"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2006.12.007"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2018.05.003"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfx147"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jid.5700943"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11638"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0803978105"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/374131a0"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.111.16.2445"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2016.12.001"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2007.06.009"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207757"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdermsci.2012.05.008"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox11061207"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.222562"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2012.09.008"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00069.2009"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-010-0328-4"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.282.5393.1497"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biophys-051013-022737"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-0563"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2004.03.024"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.2259"},{"key":"e_1_2_11_67_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201505891"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1589"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208309"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209315"},{"key":"e_1_2_11_71_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2716"},{"key":"e_1_2_11_72_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23031701"},{"key":"e_1_2_11_73_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-018-0114-z"},{"key":"e_1_2_11_74_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00648-7"},{"key":"e_1_2_11_75_1","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2891-13-17"},{"key":"e_1_2_11_76_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9051133"},{"key":"e_1_2_11_77_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-009-0776-6"},{"key":"e_1_2_11_78_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgn219"},{"key":"e_1_2_11_79_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/30.1.207"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202401950R","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T20:00:02Z","timestamp":1761681602000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202401950R"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,2]]},"references-count":78,"journal-issue":{"issue":"23","published-print":{"date-parts":[[2024,12,15]]}},"alternative-id":["10.1096\/fj.202401950R"],"URL":"https:\/\/doi.org\/10.1096\/fj.202401950r","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,2]]},"assertion":[{"value":"2024-09-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70212"}}