# Molecular basis of MED12 in the pathogenesis of uterine fibroids

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2021 · $304,079

## Abstract

PROJECT SUMMARY/ABSTRACT
Uterine leiomyomas (LM; fibroids) are monoclonal neoplasms of the myometrium (MM) and represent the
most frequent tumors in women worldwide. Although benign, they nonetheless account for significant
gynecologic and reproductive dysfunction. As no long-term non-invasive treatment option exists for LM,
deeper insight regarding tumor etiology is key to the development of newer targeted therapies.
Accordingly, this proposal is impactful as it suggests an etiologic basis for the predominant LM subtype
and further offers proof of concept for therapeutic intervention involving new druggable targets in this specific
genetic setting. LM arise from the genetic transformation of a single MM stem cell (SC) into a tumor
initiating cell (LM SC) that seeds and sustains fibroid growth through asymmetric cell divisions.
Heretofore, the dominant drivers of cell transformation have been largely identified. The most prevalent
among these, accounting for ~70% of LM, are recurrent somatic mutations in the gene encoding the MED12
subunit of Mediator, a multiprotein signal processor through which regulatory information conveyed by gene-
specific transcription factors is transduced to RNA polymerase II (Pol II). However, the impact of these
mutations on MED12 function and the molecular basis for their tumorigenic potential remain unknown. Herein,
we show that LM-linked mutations in MED12 disrupt its ability to activate Cyclin C (CycC)-dependent
kinase 8 (CDK8) in Mediator, leading to reduced site-specific RNA Pol II phosphorylation and global gene
dysregulation. We also identify genetic programs uniquely dysregulated in MED12-mutant fibroids,
leading us to hypothesize that Mediator kinase disruption as a consequence of MED12 mutations elicits
transcriptional reprogramming and altered signaling sufficient to drive MM SC transformation. We further
hypothesize that MED12-mutant LM are therapeutically susceptible to reactivation of CDK8 or
pharmacologic modulation of uniquely dysregulated signaling pathways. To test these hypotheses we will:
(1) Establish the pathogenic role of Mediator kinase disruption in MED12-mutant LM. We will ask if genetic or
chemical disruption of CDK8 (or its paralog CDK19) in Mediator can induce fibrotic transformation of MM SCs
and, conversely, if WT MED12 can restore CDK8/19 kinase activity and suppress the fibrotic phenotype of
MED12-mutant LM SCs; (2) Elucidate the pathogenic mechanism of Mediator kinase disruption in MED12-
mutant LM. We will define the biochemical basis by which MED12 mutations disrupt CycC-CDK8/19 kinase
activity and employ an integrated genome-scale approach to acquire the unique transcriptomic and epigenomic
profiles of MED12 WT and mutant LM SCs; (3) Examine the therapeutic implications of Mediator kinase
disruption in MED12-mutant LM. We will ask if reactivation of CDK8/19 or pharmacologic manipulation of
signaling pathways uniquely dysregulated in MED12-mutant LM SCs can reverse their fibrotic p...

## Key facts

- **NIH application ID:** 10145741
- **Project number:** 5R01HD087417-05
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** THOMAS G BOYER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $304,079
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145741

## Citation

> US National Institutes of Health, RePORTER application 10145741, Molecular basis of MED12 in the pathogenesis of uterine fibroids (5R01HD087417-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10145741. Licensed CC0.

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