Gain-of-Function Chromatin Remodeling Activity of Oncogenic FOXL2C134W Reprograms Glucocorticoid Receptor Occupancy to Drive Granulosa Cell Tumors

Authors

Thomas Welte
Veena K Vuttaradhi
Eleonora Y Khlebus
Allison Brodsky
Alejandra Flores Legarreta
Joseph Celestino
Reid T Powell
Clifford C Stephan
Nghi Nguyen
Jian Li
Shiro Takamatsu
Katherine Calzoncinth
Anil K Sood
David M Gershenson
P Andrew Futreal
Barrett Lawson
R Tyler Hillman

Language

English

Publication Date

3-3-2025

DOI

10.1158/0008-5472.CAN-24-2341

PMID

39652611

PMCID

PMC11873728

PubMedCentral® Posted Date

12-9-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Adult type ovarian granulosa cell tumors (AGCT) are rare malignancies with the near universal c.C402G (p.Cys134Trp) somatic mutation in FOXL2, a forkhead box family transcription factor important for ovarian function. Relapsed AGCT is incurable, but the mechanism of the unique FOXL2 mutation could confer therapeutic vulnerabilities. To identify FOXL2C134W-dependent pharmacologic synergies, we created and characterized endogenous FOXL2 isogenic AGCT cells and an AGCT tumoroid biobank. A drug screen identified that glucocorticoids promote FOXL2C134W-dependent AGCT growth. Epigenetic investigation revealed that the Cys134Trp mutation exposes latent DNA sequence-specific chromatin remodeling activity in FOXL2. FOXL2C134W-dependent chromatin remodeling activity redirected glucocorticoid receptor chromatin occupancy to drive hyaluronan synthase 2 gene expression and increase extracellular hyaluronan secretion. Treatment of AGCT models with hyaluronidase reduced viability, and dexamethasone rescued this effect. Combinatorial drug-drug interaction experiments demonstrated that dexamethasone antagonizes the potency of paclitaxel, a chemotherapy agent frequently used in the treatment of AGCT. Thus, gain-of-function pioneering activity contributes to the oncogenic mechanism of FOXL2C134W and creates a potentially targetable synergy with glucocorticoid signaling. Significance: Glucocorticoids promote granulosa cell tumor growth via epigenetic coregulation with the disease driver FOXL2C134W, providing mechanistic insight into disease oncogenesis and uncovering a potential treatment strategy.

Significance: Glucocorticoids promote granulosa cell tumor growth via epigenetic coregulation with the disease driver FOXL2C134W, providing mechanistic insight into disease oncogenesis and uncovering a potential treatment strategy.

Keywords

Female, Granulosa Cell Tumor, Forkhead Box Protein L2, Humans, Receptors, Glucocorticoid, Chromatin Assembly and Disassembly, Ovarian Neoplasms, Animals, Mice, Hyaluronan Synthases, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Mutation, Dexamethasone, Xenograft Model Antitumor Assays

Published Open-Access

yes

Recommended Citation

Welte, Thomas; Vuttaradhi, Veena K; Khlebus, Eleonora Y; et al., "Gain-of-Function Chromatin Remodeling Activity of Oncogenic FOXL2C134W Reprograms Glucocorticoid Receptor Occupancy to Drive Granulosa Cell Tumors" (2025). Faculty, Staff and Student Publications. 5674.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5674