Abrogation of USP9X is a potential strategy to decrease PEG10 levels and impede tumor progression in cutaneous T-cell lymphoma

Shan Xiong; Fengjie Liu; Jingru Sun; Shuaixin Gao; Catherine C L Wong; Ping Tu; Yang Wang

doi:10.1016/j.jid.2024.02.039

Abrogation of USP9X is a potential strategy to decrease PEG10 levels and impede tumor progression in cutaneous T-cell lymphoma

J Invest Dermatol. 2024 Apr 25:S0022-202X(24)00307-5. doi: 10.1016/j.jid.2024.02.039. Online ahead of print.

Authors

Shan Xiong¹, Fengjie Liu¹, Jingru Sun¹, Shuaixin Gao², Catherine C L Wong³, Ping Tu¹, Yang Wang⁴

Affiliations

¹ Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China;; Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China;; National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China.
² Department of Human Sciences & James Comprehensive Cancer Center,The Ohio State University, Columbus, OH, 43210, USA.
³ Clinical Research Institute, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, 100730, Beijing.
⁴ Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China;; Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China;; National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China;. Electronic address: yangwang_dr@bjmu.edu.cn.

PMID: 38677662
DOI: 10.1016/j.jid.2024.02.039

Abstract

Advanced-stage cutaneous T-cell lymphomas (CTCL) are notorious for its highly aggressive behavior, resistance to conventional treatments and poor prognosis, particularly when large-cell transformation (LCT) occurs. Paternally expressed gene 10 (PEG10) has been recently proposed as a potent driver for LCT in CTCL. However, the targeting of PEG10 continues to present a formidable clinical challenge that has yet to be addressed. Here we report an important post-translational regulatory mechanism of PEG10 in CTCL. Ubiquitin-specific protease 9X (USP9X), a deubiquitinase, interacted with and deubiquitinated PEG10, thereby stabilizing PEG10. Knockdown of USP9X or pharmacological targeting of USP9X resulted in a prominent downregulation of PEG10 and its downstream pathway in CTCL. Moreover, USP9X inhibition conferred tumor cell growth disadvantage and enhanced apoptosis in vitro, an effect that occurred in part through its regulation on PEG10. Furthermore, we demonstrated that inhibition of USP9X obviously restrained CTCL tumor growth in vivo, and that high expression of USP9X is associated with poor survival in CTCL patients. Collectively, our findings uncover USP9X as a key post-translational regulator in the stabilization of PEG10 and suggest that targeting PEG10 stabilization through USP9X inhibition may represent a promising therapeutic strategy for advanced-stage CTCL.

Keywords: Deubiquitinase; IP-MS; Mycosis fungoides; Post-translational modification.