Protein arginine methyltransferase 5 is essential for oncogene product EWSR1-ATF1-mediated gene transcription in clear cell sarcoma.
Protein arginine methyltransferase 5 is essential for oncogene product EWSR1-ATF1-mediated gene transcription in clear cell sarcoma.
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DOI：
10.1016/j.jbc.2022.102434
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发表时间：
2022-10
影响因子：
4.8
通讯作者：
Xiao, Xiangshu
中科院分区：
文献类型：
--
作者：
Li, Bingbing X.;David, Larry L.;Davis, Lara E.;Xiao, Xiangshu
Transcription dysregulation is common in sarcomas driven by oncogenic transcription factors. Clear cell sarcoma of soft tissue (CCSST) is a rare sarcoma with poor prognosis presently with no therapy. It is characterized by a balanced t(12;22) (q13;q12) chromosomal translocation, resulting in a fusion of the Ewing’s sarcoma gene EWSR1 with activating transcription factor 1 (ATF1) to give an oncogene EWSR1-ATF1. Unlike normal ATF1, whose transcription activity is dependent on phosphorylation, EWSR1-ATF1 is constitutively active to drive ATF1-dependent gene transcription to cause tumorigenesis. No EWSR1-ATF1-targeted therapies have been identified due to the challenges in targeting intracellular transcription factors. Through proteomics screening to identify potential druggable targets for CCSST, we discovered protein arginine methyltransferase 5 (PRMT5) as a novel protein to interact with EWSR1-ATF1. PRMT5 is a type II protein arginine methyltransferase to symmetrically dimethylate arginine residues in substrate proteins to regulate a diverse range of activities including gene transcription, RNA splicing, and DNA repair. We found that PRMT5 enhances EWSR1-ATF1-mediated gene transcription to sustain CCSST cell proliferation. Genetic silencing of PRMT5 in CCSST cells resulted in severely impaired cell proliferation and EWSR1-ATF1-driven transcription. Furthermore, we demonstrate that the clinical-stage PRMT5 inhibitor JNJ-64619178 potently and efficaciously inhibited CCSST cell growth in vitro and in vivo. These results provide new insights into PRMT5 as a transcription regulator and warrant JNJ-64619178 for further clinical development to treat CCSST patients.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
3.2
作者：
Li, Bingbing X.;Xiao, Xiangshu
通讯作者：
Xiao, Xiangshu
影响因子：
8
作者：
Feng, L;Lee, KAW
通讯作者：
Lee, KAW
影响因子：
3.4
作者：
Eng, Jimmy K.;Jahan, Tahmina A.;Hoopmann, Michael R.
通讯作者：
Hoopmann, Michael R.
影响因子：
7.3
作者：
McKinney, David C.;McMillan, Brian J.;Ranaghan, Matthew;Moroco, Jamie A.;Brousseau, Merissa;Mullin-Bernstein, Zachary;O'Keefe, Meghan;McCarren, Patrick;Mesleh, Michael F.;Mulvaney, Kathleen M.;Robinson, Foxy;Singh, Ritu;Bajrami, Besnik;Wagner, Florence F.;Hilgraf, Robert;Drysdale, Martin J.;Campbell, Arthur J.;Skepner, Adam;Timm, David E.;Porter, Dale;Kaushik, Virendar K.;Sellers, William R.;Ianari, Alessandra
通讯作者：
Ianari, Alessandra