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

in The Journal of investigative dermatology by Shan Xiong, Fengjie Liu, Jingru Sun, Shuaixin Gao, Catherine C L Wong, Ping Tu, Yang Wang

TLDR

  • The study found that a protein called USP9X helps keep another protein called PEG10 stable in advanced-stage skin cancer cells. By targeting USP9X, researchers think they may have found a new way to treat this type of cancer.

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.

Overview

  • The study investigates the role of Ubiquitin-specific protease 9X (USP9X) in the stabilization of Paternally expressed gene 10 (PEG10) in advanced-stage cutaneous T-cell lymphomas (CTCL).
  • The study aims to identify a potential therapeutic strategy for advanced-stage CTCL by targeting PEG10 stabilization through USP9X inhibition.

Comparative Analysis & Findings

  • The study found that USP9X 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. USP9X inhibition conferred tumor cell growth disadvantage and enhanced apoptosis in vitro, an effect that occurred in part through its regulation on PEG10. In vivo, inhibition of USP9X restrained CTCL tumor growth. High expression of USP9X is associated with poor survival in CTCL patients.

Implications and Future Directions

  • The study's findings suggest that targeting PEG10 stabilization through USP9X inhibition may represent a promising therapeutic strategy for advanced-stage CTCL. Future research should focus on developing USP9X inhibitors for clinical use and further investigation of the downstream pathway regulated by PEG10 in CTCL.