SIX1 Reprograms Myogenic Transcription Factors to Maintain the Rhabdomyosarcoma Undifferentiated State

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2022 Feb 2

PMID 35108532

Authors

Jessica Y Hsu

Etienne P Danis

Stephanie Nance

Jenean H OBrien

Annika L Gustafson

Veronica M Wessells

Andrew E Goodspeed

Jared C Talbot

Sharon L Amacher

Paul Jedlicka

Joshua C Black

James C Costello

Adam D Durbin

Kristin B Artinger

Heide L Ford

Affiliations

Soon will be listed here.

Abstract

Rhabdomyosarcoma (RMS) is a pediatric muscle sarcoma characterized by expression of the myogenic lineage transcription factors (TFs) MYOD1 and MYOG. Despite high expression of these TFs, RMS cells fail to terminally differentiate, suggesting the presence of factors that alter their functions. Here, we demonstrate that the developmental TF SIX1 is highly expressed in RMS and critical for maintaining a muscle progenitor-like state. SIX1 loss induces differentiation of RMS cells into myotube-like cells and impedes tumor growth in vivo. We show that SIX1 maintains the RMS undifferentiated state by controlling enhancer activity and MYOD1 occupancy at loci more permissive to tumor growth over muscle differentiation. Finally, we demonstrate that a gene signature derived from SIX1 loss correlates with differentiation status and predicts RMS progression in human disease. Our findings demonstrate a master regulatory role of SIX1 in repression of RMS differentiation via genome-wide alterations in MYOD1 and MYOG-mediated transcription.

Citing Articles

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