CASZ1 induces skeletal muscle and rhabdomyosarcoma differentiation through a feed-forward loop with MYOD and MYOG

Zhihui Liu (), Xiyuan Zhang, Haiyan Lei, Norris Lam, Sakereh Carter, Oliver Yockey, Max Xu, Arnulfo Mendoza, Edjay R. Hernandez, Jun S. Wei, Javed Khan, Marielle E. Yohe, Jack F. Shern and Carol J. Thiele ()
Additional contact information
Zhihui Liu: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute
Xiyuan Zhang: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute
Haiyan Lei: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute
Norris Lam: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute
Sakereh Carter: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute
Oliver Yockey: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute
Max Xu: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute
Arnulfo Mendoza: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute
Edjay R. Hernandez: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute
Jun S. Wei: Genetics Branch, Center for Cancer Research, National Cancer Institute
Javed Khan: Genetics Branch, Center for Cancer Research, National Cancer Institute
Marielle E. Yohe: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute
Jack F. Shern: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute
Carol J. Thiele: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Embryonal rhabdomyosarcoma (ERMS) is a childhood cancer that expresses myogenic master regulatory factor MYOD but fails to differentiate. Here, we show that the zinc finger transcription factor CASZ1 up-regulates MYOD signature genes and induces skeletal muscle differentiation in normal myoblasts and ERMS. The oncogenic activation of the RAS-MEK pathway suppresses CASZ1 expression in ERMS. ChIP-seq, ATAC-seq and RNA-seq experiments reveal that CASZ1 directly up-regulates skeletal muscle genes and represses non-muscle genes through affecting regional epigenetic modifications, chromatin accessibility and super-enhancer establishment. Next generation sequencing of primary RMS tumors identified a single nucleotide variant in the CASZ1 coding region that potentially contributes to ERMS tumorigenesis. Taken together, loss of CASZ1 activity, due to RAS-MEK signaling or genetic alteration, impairs ERMS differentiation, contributing to RMS tumorigenesis.

Date: 2020
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DOI: 10.1038/s41467-020-14684-4

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