2. Academic Validation
  3. USP40 promotes hepatocellular carcinoma progression through a YAP/USP40 positive feedback loop

USP40 promotes hepatocellular carcinoma progression through a YAP/USP40 positive feedback loop

  • Cancer Lett. 2024 May 1:589:216832. doi: 10.1016/j.canlet.2024.216832.
Huanye Mo 1,  Runtian Li 1,  Nan Yang 2,  Jiaqi Han 3,  Xuelian Xiao 1,  Yilei Zhang 3,  Zhengtao Xiao 3,  Lianying Jiao 3,  Qiuran Xu 4,  Kangsheng Tu 5
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
  • 2 Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
  • 3 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China.
  • 4 Zhejiang Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, China. Electronic address: xuqiuran@hmc.edu.cn.
  • 5 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. Electronic address: tks0912@foxmail.com.
PMID: 38537774 DOI: 10.1016/j.canlet.2024.216832
Abstract

Yes-associated protein (YAP) is an essential driver of hepatocellular carcinoma (HCC) progression and the ubiquitin-proteasome system controls its abundance. However, the role of Ubiquitin-Specific Protease 40 (USP40) in YAP stability remains unclear. Here, USP40 was first identified as a novel regulator of YAP abundance and its target genes in HCC cells. USP40 interacted with YAP to remove the lysine 48 (K48)-linked polyubiquitination of YAP at K252 and K315 sites, thereby maintaining YAP stability. USP40 facilitated the proliferation, colony formation, migration and spheroid formation of HCC cells in vitro and promoted HCC growth in vivo in a YAP-dependent manner. In turn, YAP transcriptionally activated USP40 expression in HCC cells. RNA Sequencing analysis showed that about 37% of USP40-regulated genes overlapped with YAP-regulated genes. Interestingly, stiffness-induced USP40 upregulation was abolished by YAP knockdown, and USP40 knockdown attenuated stiffness-induced YAP accumulation in HCC cells. Clinical data demonstrated that USP40 was positively associated with YAP expression in HCC tissues and its high expression indicated a poor prognosis. In conclusion, the USP40/YAP positive feedback loop contributes to HCC progression, suggesting that USP40 may be a promising drug target for anti-HCC.

Keywords

Hepatocellular carcinoma; Stiffness; Tumor progression; USP40; YAP.

Figures
Products