SMARCB1 deletion in atypical teratoid rhabdoid tumors results in human endogenous retrovirus K (HML-2) expression

• Published in: Scientific reports Vol. 11; no. 1; p. 12893
• Main Authors: Doucet-O’Hare, Tara T., DiSanza, Brianna L., DeMarino, Catherine, Atkinson, Abigail L., Rosenblum, Jared S., Henderson, Lisa J., Johnson, Kory R., Kowalak, Jeffrey, Garcia-Montojo, Marta, Allen, Sariah J., Orr, Brent A., Santi, Mariarita, Wang, Tongguang, Fathi, Saeed, Lee, Myoung Hwa, Sampson, Kevon, Li, Wenxue, Zhuang, Zhengping, Nath, Avindra
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 18.06.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Cell death; Cell proliferation; Central nervous system; Chromatin; CRISPR; Gene deletion; Genomes; Immunoprecipitation; MAP kinase; Myc protein; Neural stem cells; Pluripotency; siRNA; Stem cells; Tumor suppressor genes; Tumorigenesis; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-92223-x

Abstract Atypical Teratoid Rhabdoid Tumor (AT/RT) is a rare pediatric central nervous system cancer often characterized by deletion or mutation of SMARCB1 , a tumor suppressor gene. In this study, we found that SMARCB1 regulates Human Endogenous Retrovirus K (HERV-K, subtype HML-2) expression. HML-2 is a repetitive element scattered throughout the human genome, encoding several intact viral proteins that have been associated with stem cell maintenance and tumorigenesis. We found HML-2 env expression in both the intracellular and extracellular compartments in all AT/RT cell lines (n = 4) and in 95% of AT/RT patient tissues (n = 37) evaluated. SMARCB1 knock-down in neural stem cells (NSCs) led to an upregulation of HML-2 transcription. We found that SMARCB1 binds adjacent to the HML-2 promoter, repressing its transcription via chromatin immunoprecipitation; restoration of SMARCB1 expression in AT/RT cell lines significantly downregulated HML-2 expression. Further, targeted downregulation of HML-2 transcription via CRISPR-dCas9 coupled with suppressor proteins led to cellular dispersion, decreased proliferation , and cell death in vitro. HML-2 knock-down with shRNA, siRNA, and CRISPR-dCas9 significantly decreased Ras expression as measured by qRT-PCR, suggesting that HML-2 modulates MAPK/ERK signaling in AT/RT cells. Overexpression of NRAS was sufficient to restore cellular proliferation, and MYC, a transcription factor downstream of NRAS , was bound to the HERV-K LTR significantly more in the absence of SMARCB1 expression in AT/RT cells. We show a mechanism by which these undifferentiated tumors remain pluripotent, and we demonstrate that their formation is aided by aberrant HML-2 activation, which is dependent on SMARCB1 and its interaction with MYC.