Language

English

Publication Date

8-1-2024

Journal

Nature

DOI

10.1038/s41586-024-07751-z

PMID

39085609

PMCID

PMC11951423

PubMedCentral® Posted Date

3-28-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Bidirectional communication between tumors and neurons has emerged as a key facet of the tumor microenvironment that drives malignancy1,2. Another hallmark feature of cancer is epigenomic dysregulation, where alterations in gene expression influences cell states and interactions with the tumor microenvironment3. Ependymoma (EPN) is a pediatric brain tumor that relies on epigenomic remodeling to engender malignancy4,5; how these epigenetic mechanisms intersect with extrinsic neuronal signaling during EPN tumor progression is unknown. Here we show that activity of serotonergic neurons regulates EPN tumorigenesis, while serotonin itself also serves as an activating modification on histones. We found that inhibition of histone serotonylation blocks EPN tumorigenesis and regulates expression of a core set of developmental transcription factors (TFs). High-throughput, in vivo screening of these TFs revealed that ETV5 promotes EPN tumorigenesis and functions by enhancing repressive chromatin states. Neuropeptide Y (NPY) is amongst the genes repressed by ETV5 and its overexpression suppresses EPN tumor progression and tumor-associated network hyperactivity via synaptic remodeling. Collectively, these studies identify histone serotonylation as a key driver of EPN tumorigenesis, while further revealing how neuronal signaling, neuro-epigenomics, and developmental programs are intertwined to drive malignancy in brain cancer.

Keywords

Animals, Female, Humans, Male, Mice, Brain Neoplasms, Carcinogenesis, Cell Line, Tumor, Chromatin, Disease Progression, DNA-Binding Proteins, Ependymoma, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Histones, Transcription Factors, Tumor Microenvironment, Serotonergic Neurons, Serotonin

Published Open-Access

yes

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