{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T18:55:57Z","timestamp":1781895357851,"version":"3.54.5"},"posted":{"date-parts":[[2024,9,9]]},"group-title":"Cell Biology","reference-count":62,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T00:00:00Z","timestamp":1725840000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,9,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Uterine fibroids (leiomyomas), benign tumors of the myometrial smooth muscle layer, are present in over 75% of women, often causing severe pain, menorrhagia and reproductive dysfunction. The molecular pathogenesis of fibroids is poorly understood. We previously showed that the loss of REST (\n                  <jats:underline>RE<\/jats:underline>\n                  -1\n                  <jats:underline>S<\/jats:underline>\n                  ilencing\n                  <jats:underline>T<\/jats:underline>\n                  ranscription factor), a tumor suppressor, in fibroids leads to activation of PI3K\/AKT-mTOR pathway. We report here a critical link between estrogen receptor alpha (ER\u03b1) and the loss of REST,\n                  <jats:italic>via<\/jats:italic>\n                  PRICKLE1. PRICKLE1 expression is markedly lower in leiomyomas, and the suppression of PRICKLE1 significantly down regulates REST protein levels. Conversely, overexpression of PRICKLE1 resulted in the restoration of REST in cultured primary leiomyoma smooth muscle cells (LSMCs). Crucially, mice exposed neonatally to environmental estrogens, proven risk factors for fibroids, expressed lower levels of PRICKLE1 and REST in the myometrium. Using mice that lack either endogenous estrogen (\n                  <jats:italic>\n                    Lhb\n                    <jats:sup>-\/-<\/jats:sup>\n                  <\/jats:italic>\n                  mice) or ER\u03b1 (\n                  <jats:italic>\n                    Esr1\n                    <jats:sup>-\/-<\/jats:sup>\n                  <\/jats:italic>\n                  mice), we demonstrate that\n                  <jats:italic>Prickle1<\/jats:italic>\n                  expression in the myometrium is suppressed by estrogen through ER\u03b1. Enhancer of zeste homolog 2 (EZH2) is known to participate in the repression of specific ER\u03b1 target genes. Uterine leiomyomas express increased levels of EZH2 that inversely correlate with the expression of PRICKLE1. Using chromatin immunoprecipitation, we provide evidence for association of EZH2 with the\n                  <jats:italic>PRICKLE1<\/jats:italic>\n                  promoter and for hypermethylation of H3K27 within the regulatory region of\n                  <jats:italic>PRICKLE1<\/jats:italic>\n                  in leiomyomas. Additionally, siRNA mediated knockdown of EZH2 leads to restoration of PRICKLE1 in LSMCs. Collectively, our results identify a novel link between estrogen exposure and PRICKLE1\/REST-regulated tumorigenic pathways in leiomyomas.\n                <\/jats:p>","DOI":"10.1101\/2024.09.09.612036","type":"posted-content","created":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T03:15:14Z","timestamp":1725938114000},"source":"Crossref","is-referenced-by-count":5,"title":["Estrogen receptor alpha mediated repression of PRICKLE1 destabilizes REST and promotes uterine fibroid pathogenesis"],"prefix":"10.64898","author":[{"given":"Michelle M.","family":"McWilliams","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7777-6526","authenticated-orcid":false,"given":"Faezeh","family":"Koohestani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5741-2159","authenticated-orcid":false,"given":"Wendy N.","family":"Jefferson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2097-135X","authenticated-orcid":false,"given":"Sumedha","family":"Gunewardena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2189-3771","authenticated-orcid":false,"given":"Kavya","family":"Shivashankar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riley A.","family":"Wertenberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6440-7086","authenticated-orcid":false,"given":"Carmen J.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7666-5493","authenticated-orcid":false,"given":"T.","family":"Rajendra Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4178-146X","authenticated-orcid":false,"given":"Vargheese M.","family":"Chennathukuzhi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024091105150643000_2024.09.09.612036v1.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1112063"},{"key":"2024091105150643000_2024.09.09.612036v1.2","doi-asserted-by":"publisher","DOI":"10.1093\/ajcp\/94.4.435"},{"issue":"1","key":"2024091105150643000_2024.09.09.612036v1.3","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1067\/mob.2003.99","article-title":"High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. 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