Heterozygous Kmt2d Loss Diminishes Enhancers To Render Medulloblastoma Cells Vulnerable to Combinatory Inhibition of LSD1 and OXPHOS

Authors

Shilpa S Dhar
Calena Brown
Ali Rizvi
Lauren Reed
Sivareddy Kotla
Constantin Zod
Janak Abraham
Jun-Ichi Abe
Veena Rajaram
Kaifu Chen
Min Gyu Lee

Publication Date

5-27-2025

Journal

Cell Reports

DOI

10.1016/j.celrep.2025.115619

PMID

40286267

Abstract

The histone H3 lysine 4 (H3K4) methyltransferase KMT2D (also called MLL4) is one of the most frequently mutated epigenetic modifiers in many cancers, including medulloblastoma (MB). Notably, heterozygous KMT2D loss frequently occurs in MB and other cancers. However, its oncogenic role remains largely uncharacterized. Here, we show that heterozygous Kmt2d loss in murine cerebellar regions promotes MB genesis driven by heterozygous loss of the MB-suppressor gene Ptch via the upregulation of tumor-promoting programs (e.g., oxidative phosphorylation [OXPHOS]). Downregulation of the transcription-repressive tumor suppressor NCOR2 by heterozygous Kmt2d loss, along with Ptch

Keywords

Animals, Medulloblastoma, Histone Demethylases, Mice, Oxidative Phosphorylation, Enhancer Elements, Genetic, Heterozygote, Cell Line, Tumor, Humans, Histone-Lysine N-Methyltransferase, Cerebellar Neoplasms, DNA-Binding Proteins, Histones, Patched-1 Receptor, Gene Expression Regulation, Neoplastic, Myeloid-Lymphoid Leukemia Protein

Published Open-Access

yes

Recommended Citation

Dhar, Shilpa S; Brown, Calena; Rizvi, Ali; et al., "Heterozygous Kmt2d Loss Diminishes Enhancers To Render Medulloblastoma Cells Vulnerable to Combinatory Inhibition of LSD1 and OXPHOS" (2025). Faculty, Staff and Student Publications. 4343.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4343