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- Title
CASZ1 induces skeletal muscle and rhabdomyosarcoma differentiation through a feed-forward loop with MYOD and MYOG.
- Authors
Liu, Zhihui; Zhang, Xiyuan; Lei, Haiyan; Lam, Norris; Carter, Sakereh; Yockey, Oliver; Xu, Max; Mendoza, Arnulfo; Hernandez, Edjay R.; Wei, Jun S.; Khan, Javed; Yohe, Marielle E.; Shern, Jack F.; Thiele, Carol J.
- 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. Embryonal rhabdomyosarcoma (ERMS) is a childhood cancer with impaired myogenic differentiation despite the presence of myogenic transcription factors. Here, the authors show that CASZ1 directly regulates these myogenic factors and the loss of CASZ1 is due to RAS-MEK signaling in ERMS.
- Subjects
CHILDHOOD cancer; ZINC-finger proteins; TRANSCRIPTION factors; RHABDOMYOSARCOMA; EPIGENOMICS; SKELETAL muscle; MYOBLASTS; FACIOSCAPULOHUMERAL muscular dystrophy
- Publication
Nature Communications, 2020, Vol 11, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-14684-4