The P-MYH9/USP22/Hif-1α Axis Promotes Lenvatinib Resistance and Cancer Stemness in Hepatocellular Carcinoma

Authors

Qiaonan Shan
Lu Yin
Qifan Zhan
Jiongjie Yu
Sheng Pan
Jianyong Zhuo
Wei Zhou
Jiaqi Bao
Lincheng Zhang
Jiachen Hong
Jianan Xiang
Qingyang Que
Kangchen Chen
Shengjun Xu
Jingrui Wang
Yangbo Zhu
Bin He
Jingbang Wu
Haiyang Xie
Shusen Zheng
Tingting Feng
Sunbin Ling
Xiao Xu

Publication Date

9-19-2024

Journal

Signal Transduction and Targeted Therapy

Abstract

Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma (HCC). A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed. In this study, we aimed to dissect the underlying mechanism of lenvatinib resistance (LR) and provide effective treatment strategies. We established an HCC model of acquired LR. Cell counting, migration, self-renewal ability, chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells. Molecular and biochemical strategies such as RNA-sequencing, immunoprecipitation, mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms. Patient-derived HCC models and HCC samples from patients were used to demonstrate clinical significance. We identified that increased cancer stemness driven by the hypoxia-inducible factor-1α (HIF-1α) pathway activation is responsible for acquired LR in HCC. Phosphorylated non-muscle myosin heavy chain 9 (MYH9) at Ser1943, p-MYH9 (Ser1943), could recruit ubiquitin-specific protease 22 (USP22) to deubiquitinate and stabilize HIF-1α in lenvatinib-resistant HCC. Clinically, p-MYH9 (Ser1943) expression was upregulated in HCC samples, which predicted poor prognosis and LR. A casein kinase-2 (CK2) inhibitor and a USP22 inhibitor effectively reversed LR in vivo and in vitro. Therefore, the p-MYH9 (Ser1943)/USP22/HIF-1α axis is critical for LR and cancer stemness. For the diagnosis and treatment of LR in HCC, p-MYH9 (Ser1943), USP22, and HIF-1α might be valuable as novel biomarkers and targets.

Keywords

Carcinoma, Hepatocellular, Humans, Quinolines, Liver Neoplasms, Hypoxia-Inducible Factor 1, alpha Subunit, Phenylurea Compounds, Drug Resistance, Neoplasm, Ubiquitin Thiolesterase, Neoplastic Stem Cells, Myosin Heavy Chains, Mice, Cell Line, Tumor, Animals, Gene Expression Regulation, Neoplastic, Male, Cancer stem cells, Drug development, Tumour biomarkers

Comments

Supplementary Materials

Data Availability Statement

PMID: 39300073