Impact of MED12 mutation and CDK8 activity on uterine leiomyoma growth and response to gonadotropin-releasing hormone agonist treatment

Sep 29, 2026

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MED12 exon 2 mutation is the most frequent genetic alteration in uterine leiomyomas, and MED12 wild-type tumors show greater growth potential than mutant tumors, implying the mutation constrains leiomyoma expansion. MED12 forms a complex with CDK8 and contributes to phosphorylation of RNA polymerase II, yet the mechanism linking MED12 status to leiomyoma growth and to GnRH-agonist response remains unclear. The study evaluates CDK8 activity, proliferation, and apoptosis and tests CDK8 inhibitors in primary cultures.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Abstract

Study aims and grouping strategy

CDK8 activity and cellular assays

Key findings

Introduction

Clinical context and treatment limitations

Genetic background of leiomyomas

OPEN ACCESS Citation: Tanioka S, Asano R, Ota Y, Nagai K, Takenaka K, Mizushima T, et al. (2026) Impact of MED12 mutation and CDK8 activity on uterine leiomyoma growth and response to gonadotropin-releasing hormone agonist treatment. PLoS One 21(1): e0338485. [https://](https://)[ ](https://)[doi.org/10.1371/journal.pone.0338485](doi.org/10.1371/journal.pone.0338485) Editor: Kazunori Nagasaka, Teikyo University, School of Medicine, JAPAN Received: May 21, 2025 Accepted: November 24, 2025 Published: January 6, 2026 Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: [https://doi.org/10.1371/journal](https://doi.org/10.1371/journal). pone.0338485 Copyright: © 2026 Tanioka et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, RESEARCH ARTICLE Impact of MED12 mutation and CDK8 activity on uterine leiomyoma growth and response to gonadotropin-releasing hormone agonist treatment Saki Tanioka1, Ryoko Asano1,2*, Yukihide Ota1, Koichi Nagai1, Katsuya Takenaka3,4, Taichi Mizushima1, Yohei Miyagi3, Etsuko Miyagi1 1 Department of Obstetrics, Gynecology and Molecular Reproductive Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan, 2 Department of Gynecology, Yokohama City University Medical Center, Yokohama, Japan, 3 Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan, 4 TR Company, Shin Nippon Biomedical Laboratories, Ltd. , Kagoshima, Japan * [new_official_asano@hotmail.co.jp](new_official_asano@hotmail.co.jp) Abstract MED12 exon 2 mutation is the most frequent mutation associated with uterine leiomyomas. MED12 wild-type leiomyomas have a higher growth potential than mutant leiomyomas, suggesting that the mutation limits leiomyoma growth. MED12 forms a complex with CDK8 and is involved in the phosphorylation of RNA polymerase II, playing a role in transcriptional regulation. However, its mechanism of action in leiomyoma growth is not clear. We aimed to clarify the relationship between MED12 mutation status, response to gonadotropin-releasing hormone (GnRH) agonist treatment, and CDK8 activity in leiomyomas. We also examined the effects of CDK8 inhibitors on primary cultured uterine leiomyoma cells. We classified 44 surgically removed uterine leiomyomas into four groups according to GnRH agonist use and MED12 mutation status. CDK8 was co-immunoprecipitated from leiomyoma tissue extracts using MED12 antibody to test its kinase activity in vitro, and the amount of phosphorylated substrate was measured. Cell proliferation and apoptosis of primary cultured MED12 wild-type leiomyoma cells were evaluated in the presence of a CDK8 inhibitor and sex steroid hormones. Of the 44 leiomyomas tested, 11 MED12 wild-type leiomyomas without preoperative GnRH agonist treatment had significantly higher CDK8 activity than nine GnRH agonist-treated MED12 wild-type leiomyomasand 15 leiomyomas with MED12 mutations without GnRH agonist treatment. Treatment of primary cultured MED12 wild-type cells with CDK8 inhibitors significantly inhibited cell growth and increased apoptosis. MED12 wild-type leiomyoma cells without GnRH agonist treatment showed high CDK8 activity, and inhibition of CDK8 activity suppressed cell growth in vitro. PLOS One | [https://doi.org/10.1371/journal.pone.0338485](https://doi.org/10.1371/journal.pone.0338485) January 6, 2026 1 / 16 and reproduction in any medium, provided the original author and source are credited. Data availability statement: All relevant data are within the paper and its Supporting information files. Funding: This study was supported in part by the Kihara Memorial Yokohama Found

FAQs

What is the main purpose of this study?

To clarify how MED12 mutation status relates to uterine leiomyoma growth, CDK8 activity, and response to GnRH-agonist treatment, and to assess the effects of CDK8 inhibitors on primary cultured leiomyoma cells.

How were the leiomyomas classified for analysis?

The researchers classified 44 surgically removed uterine leiomyomas into four groups based on whether patients used GnRH agonists preoperatively and whether the tumors carried MED12 mutations.

What effect did CDK8 inhibitors have on MED12 wild-type cells?

In primary cultured MED12 wild-type leiomyoma cells, CDK8 inhibitor treatment significantly inhibited cell growth and increased apoptosis, indicating that CDK8 activity supports tumor cell survival and proliferation in vitro.

Sep 29, 2026

Upload by jayni