Cell-type dependent enhancer binding of the EWS/ATF1 fusion gene in clear cell sarcomas

• Komura, Shingo

• Ito, Kenji

• Ohta, Sho

• Ukai, Tomoyo

• Kabata, Mio

• Itakura, Fumiaki

• Semi, Katsunori

• Matsuda, Yutaka

• Hashimoto, Kyoichi

• Shibata, Hirofumi

• Sone, Masamitsu

• Jo, Norihide

• Sekiguchi, Kazuya

• Ohno, Takatoshi

• Akiyama, Haruhiko

• Shimizu, Katsuji

• Woltjen, Knut

• Ozawa, Manabu

• Toguchida, Junya

• Yamamoto, Takuya

• Yamada, Yasuhiro

Abstract

Clear cell sarcoma (CCS) is a rare soft tissue sarcoma caused by the EWS/ATF1 fusion gene. Here, we established induced pluripotent stem cells (iPSCs) from EWS/ATF1-controllable murine CCS cells harboring sarcoma-associated genetic abnormalities. Sarcoma-iPSC mice develop secondary sarcomas immediately after EWS/ATF1 induction, but only in soft tissue. EWS/ATF1 expression induces oncogene-induced senescence in most cell types in sarcoma-iPSC mice but prevents it in sarcoma cells. We identify Tppp3-expressing cells in peripheral nerves as a cell-of-origin for these sarcomas. We show cell type-specific recruitment of EWS/ATF1 to enhancer regions in CCS cells. Finally, epigenetic silencing at these enhancers induces senescence and inhibits CCS cell growth through altered EWS/ATF1 binding. Together, we propose that distinct responses to premature senescence are the basis for the cell type-specificity of cancer development.

Journal

• Nature Communications

  Nature Communications 10 2019-09-05

  Springer Nature

Keywords

• Cancer models
• Reprogramming

Details

• CRID: 1050564288434062848
• NII Article ID: 120006719352
• ISSN: 20411723
• HANDLE: 2433/243965
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • CiNii Articles