1. Academic Validation
  2. 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

  • J Biol Chem. 2022 Aug 27;298(10):102434. doi: 10.1016/j.jbc.2022.102434.
Bingbing X Li 1 Larry L David 2 Lara E Davis 3 Xiangshu Xiao 4
Affiliations

Affiliations

  • 1 Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, USA. Electronic address: lib@ohsu.edu.
  • 2 Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, USA.
  • 3 Knight Cancer Institute, Oregon Health & Science University, Portland, USA; Division of Hematology and Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, USA.
  • 4 Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, USA. Electronic address: xiaoxi@ohsu.edu.
Abstract

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.

Keywords

EWSR1-ATF1; JNJ-64619178; PRMT5; clear cell sarcoma; inhibitor; transcription.

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