SMARCB1 deletion in atypical teratoid rhabdoid tumors results in human endogenous retrovirus K (HML-2) expression
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...
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2021
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oai:doaj.org-article:b606f3bbb7b5473bafc41a2148c765eb2021-12-02T17:23:03ZSMARCB1 deletion in atypical teratoid rhabdoid tumors results in human endogenous retrovirus K (HML-2) expression10.1038/s41598-021-92223-x2045-2322https://doaj.org/article/b606f3bbb7b5473bafc41a2148c765eb2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92223-xhttps://doaj.org/toc/2045-2322Abstract 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.Tara T. Doucet-O’HareBrianna L. DiSanzaCatherine DeMarinoAbigail L. AtkinsonJared S. RosenblumLisa J. HendersonKory R. JohnsonJeffrey KowalakMarta Garcia-MontojoSariah J. AllenBrent A. OrrMariarita SantiTongguang WangSaeed FathiMyoung Hwa LeeKevon SampsonWenxue LiZhengping ZhuangAvindra NathNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021) |
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Medicine R Science Q Tara T. Doucet-O’Hare Brianna L. DiSanza Catherine DeMarino Abigail L. Atkinson Jared S. Rosenblum Lisa J. Henderson Kory R. Johnson Jeffrey Kowalak Marta Garcia-Montojo Sariah J. Allen Brent A. Orr Mariarita Santi Tongguang Wang Saeed Fathi Myoung Hwa Lee Kevon Sampson Wenxue Li Zhengping Zhuang Avindra Nath SMARCB1 deletion in atypical teratoid rhabdoid tumors results in human endogenous retrovirus K (HML-2) expression |
| description |
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. |
| format |
article |
| author |
Tara T. Doucet-O’Hare Brianna L. DiSanza Catherine DeMarino Abigail L. Atkinson Jared S. Rosenblum Lisa J. Henderson Kory R. Johnson Jeffrey Kowalak Marta Garcia-Montojo Sariah J. Allen Brent A. Orr Mariarita Santi Tongguang Wang Saeed Fathi Myoung Hwa Lee Kevon Sampson Wenxue Li Zhengping Zhuang Avindra Nath |
| author_facet |
Tara T. Doucet-O’Hare Brianna L. DiSanza Catherine DeMarino Abigail L. Atkinson Jared S. Rosenblum Lisa J. Henderson Kory R. Johnson Jeffrey Kowalak Marta Garcia-Montojo Sariah J. Allen Brent A. Orr Mariarita Santi Tongguang Wang Saeed Fathi Myoung Hwa Lee Kevon Sampson Wenxue Li Zhengping Zhuang Avindra Nath |
| author_sort |
Tara T. Doucet-O’Hare |
| title |
SMARCB1 deletion in atypical teratoid rhabdoid tumors results in human endogenous retrovirus K (HML-2) expression |
| title_short |
SMARCB1 deletion in atypical teratoid rhabdoid tumors results in human endogenous retrovirus K (HML-2) expression |
| title_full |
SMARCB1 deletion in atypical teratoid rhabdoid tumors results in human endogenous retrovirus K (HML-2) expression |
| title_fullStr |
SMARCB1 deletion in atypical teratoid rhabdoid tumors results in human endogenous retrovirus K (HML-2) expression |
| title_full_unstemmed |
SMARCB1 deletion in atypical teratoid rhabdoid tumors results in human endogenous retrovirus K (HML-2) expression |
| title_sort |
smarcb1 deletion in atypical teratoid rhabdoid tumors results in human endogenous retrovirus k (hml-2) expression |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/b606f3bbb7b5473bafc41a2148c765eb |
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