Estrogen receptor alpha mediated repression of PRICKLE1 destabilizes REST and promotes uterine fibroid pathogenesis

Michelle M. McWilliams, Faezeh Koohestani, Wendy N. Jefferson, Sumedha Gunewardena, Kavya Shivashankar, Riley A. Wertenberger, Carmen J. Williams, T. Rajendra Kumar, Vargheese Chennathukuzhi
In: bioRxiv · 2024 · doi:10.1101/2024.09.09.612036 · PMID:39314474 · W4402420357
preprint OA: green CC0 ⤵ 1 in-corpus citation
📄 Open PDF View on OpenAlex View on PubMed View at publisher
⚙ AI-generated summary by claude@2026-06, 2026-06-10 ⓘ

Estrogen receptor alpha activation represses PRICKLE1 expression via EZH2, leading to REST destabilization and promoting uterine fibroid pathogenesis.

One-sentence paraphrase of the abstract; not a substitute for reading it. No clinical advice. How this works

Abstract

ABSTRACT 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 ( RE -1 S ilencing T 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 (ERα) and the loss of REST, via 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 ( Lhb -/- mice) or ERα ( Esr1 -/- mice), we demonstrate that Prickle1 expression in the myometrium is suppressed by estrogen through ERα. Enhancer of zeste homolog 2 (EZH2) is known to participate in the repression of specific ERα 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 PRICKLE1 promoter and for hypermethylation of H3K27 within the regulatory region of PRICKLE1 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.

My notes (saved in your browser only)

Citation neighborhood (sparse)

Too few in-corpus citations on either side for a chart; here are the lists.

Cites (3)

Cited by (1)

References (61)

Cited by (1)

Source provenance

europepmc
last seen: 2026-05-20T01:45:00.602351+00:00
openalex
last seen: 2026-06-04T00:00:01.174412+00:00
License: CC0 · commercial use OK