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Transposable Elements Are Co-opted as Oncogenic Regulatory Elements by Lineage-Specific Transcription Factors in Prostate Cancer.
Grillo, Giacomo; Keshavarzian, Tina; Linder, Simon; Arlidge, Christopher; Mout, Lisanne; Nand, Ankita; Teng, Mona; Qamra, Aditi; Zhou, Stanley; Kron, Ken J; Murison, Alex; Hawley, James R; Fraser, Michael; van der Kwast, Theodorus H; Raj, Ganesh V; He, Housheng Hansen; Zwart, Wilbert; Lupien, Mathieu.
Affiliation
  • Grillo G; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Keshavarzian T; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Linder S; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • Arlidge C; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • Mout L; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Nand A; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Teng M; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Qamra A; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Zhou S; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • Kron KJ; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Murison A; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Hawley JR; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • Fraser M; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • van der Kwast TH; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Raj GV; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • He HH; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • Zwart W; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Lupien M; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Cancer Discov ; 13(11): 2470-2487, 2023 11 01.
Article in En | MEDLINE | ID: mdl-37694973
Transposable elements hold regulatory functions that impact cell fate determination by controlling gene expression. However, little is known about the transcriptional machinery engaged at transposable elements in pluripotent and mature versus oncogenic cell states. Through positional analysis over repetitive DNA sequences of H3K27ac chromatin immunoprecipitation sequencing data from 32 normal cell states, we report pluripotent/stem and mature cell state-specific "regulatory transposable elements." Pluripotent/stem elements are binding sites for pluripotency factors (e.g., NANOG, SOX2, OCT4). Mature cell elements are docking sites for lineage-specific transcription factors, including AR and FOXA1 in prostate epithelium. Expanding the analysis to prostate tumors, we identify a subset of regulatory transposable elements shared with pluripotent/stem cells, including Tigger3a. Using chromatin editing technology, we show how such elements promote prostate cancer growth by regulating AR transcriptional activity. Collectively, our results suggest that oncogenesis arises from lineage-specific transcription factors hijacking pluripotent/stem cell regulatory transposable elements. SIGNIFICANCE: We show that oncogenesis relies on co-opting transposable elements from pluripotent stem cells as regulatory elements altering the recruitment of lineage-specific transcription factors. We further discover how co-option is dependent on active chromatin states with important implications for developing treatment options against drivers of oncogenesis across the repetitive DNA. This article is featured in Selected Articles from This Issue, p. 2293.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Transcription Factors Type of study: Prognostic_studies Limits: Humans / Male Language: En Journal: Cancer Discov Year: 2023 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Transcription Factors Type of study: Prognostic_studies Limits: Humans / Male Language: En Journal: Cancer Discov Year: 2023 Document type: Article Affiliation country: Country of publication: