Journal Article

Loss of USP10 promotes hepatocellular carcinoma proliferation by regulating the serine synthesis pathway through inhibition of LKB1 activity

Ye, Yaorui, Liu, Xinyu, Tan, Guang, Yao, Jiaqi, Li, Qi, Wang, Xiaolin, Lin, Zhikun, Chen, Fating, Hu, Jinlong, Ma, Chi, Qin, Wangshu, Xu, Guowang

2024

Overview

Metabolic dysregulation is emerging as a critical factor in tumorigenesis, and reprogramming of serine metabolism has been identified as an essential factor in the progression of hepatocellular carcinoma (HCC). Studies have shown that LKB1 deficiency can activate mTOR to upregulate the serine synthesis pathway (SSP) and promote tumor progression. Our team discovered that ubiquitin‐specific protease 10 (USP10) can inhibit HCC proliferation through mTOR, but its relationship with SSP needs further investigation. The metabolite assays revealed a significant increase in serine content in HCC tissues. Through the LKB1/mTOR/activating transcription factor 4 (ATF4) axis, loss of USP10 may increase serine biosynthesis and promote the proliferation of HCC in vitro and in vivo. Furthermore, it was found that USP10 could activate LKB1 through deubiquitination. Analyzing clinical HCC tissues revealed a positive correlation between USP10 and LKB1. Additionally, those with high expression of USP10 in HCC tissues showed a better degree of tumor differentiation and longer overall survival time. Moreover, we found increased expression of both serine and its synthase in liver tumor tissues of USP10 liver‐specific KO mice. Loss of USP10 inhibits the activity of LKB1, contributing to the stimulation of the mTOR/ATF4 axis and SSP and then promoting the proliferation of HCC. This work presents a novel approach for serine‐targeted treatment in HCC. Aberrant serine synthesis plays a vital role in hepatocellular carcinoma (HCC), so finding upstream regulators that control the serine synthesis pathway (SSP) is particularly important. This study shows that ubiquitin‐specific protease 10 (USP10) plays a crucial role in regulating the expression of SSP through the LKB1/mTOR/ATF4 axis and affects the proliferation of HCC. USP10 can regulate the activity of LKB1 through deubiquitination. This study identifies new potential sites for targeting therapy in HCC.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Activating transcription factor 4 / Activating Transcription Factor 4 - genetics / Activating Transcription Factor 4 - metabolism / AMP-Activated Protein Kinase Kinases - metabolism / Animals / Biotechnology industry / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - metabolism / Carcinoma, Hepatocellular - pathology / Cell Line, Tumor / Cell Proliferation / Chromatography / Development and progression / Female / Gene Expression Regulation, Neoplastic / Hepatocellular carcinoma / Hepatoma / Humans / Kinases / Lipids / Liver / Liver cancer / Liver Neoplasms - genetics / Liver Neoplasms - metabolism / Liver Neoplasms - pathology / LKB1 / LKB1 protein / Male / Mass spectrometry / Medical research / metabolic reprogramming / Metabolism / Metabolites / Mice / Mice, Knockout / Middle Aged / Original / Plasmids / Proteases / Protein expression / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Proteins / Scientific imaging / Serine / Serine - metabolism / serine synthesis pathway / Signal Transduction / TOR protein / TOR Serine-Threonine Kinases - metabolism / Transcription factors / Tumorigenesis / Tumors / Ubiquitin / Ubiquitin Thiolesterase - genetics / Ubiquitin Thiolesterase - metabolism / USP10