Hypoxia-induced SKA3 promoted cholangiocarcinoma progression and chemoresistance by enhancing fatty acid synthesis via the regulation of PAR-dependent HIF-1a deubiquitylation

作者：Yananlan Chen, Xiao Xu, Yirui Wang, Yaodong Zhang, Tao Zhou, Wangjie Jiang, Ziyi Wang, Jiang Chang, Shuochen Liu, Ruixiang Chen, Jijun Shan, Jifei Wang, Yuming Wang, Changxian Li, Xiangcheng Li · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2023 · DOI：10.1186/s13046-023-02842-7 · 被引用次数：43 · 研究领域：Cancer, Hypoxia, and Metabolism、Cancer, Lipids, and Metabolism、Autophagy in Disease and Therapy

BACKGROUND: Spindle and kinetochore-associated complex subunit 3 (SKA3) plays an important role in cell proliferation by regulating the separation of chromosomes and their division into daughter cells. Previous studies demonstrated that SKA3 was strongly implicated in tumor development and progression. However, the roles of SKA3 in cholangiocarcinoma (CCA) and the underlying mechanisms remain unclear. METHODS: Next-generation sequencing (NGS) was performed with paired CCA tissues and normal adjacent tissues (NATs). SKA3 was chose to be the target gene because of its remarkably upregulation and unknown function in cholangiocarcinoma in TCGA datasets, GSE107943 datasets and our sequencing results. RT-PCR and immunohistochemistry staining were used to detect the expression of SKA3 in paired CCA tissues and normal adjacent tissues. The SKA3 knockdown and overexpression cell line were constructed by small interfering RNA and lentivirus vector transfection. The effect of SKA3 on the proliferation of cholangiocarcinoma under hypoxic conditions was detected by experiments in vitro and in vivo. RNA-seq was used to find out the differentially expressed pathways in cholangiocarcinoma proliferation under hypoxia regulated by SKA3. IP/MS analysis and Western blot assays were used to explore the specific mechanism of SKA3 in regulating the expression of HIF-1a under hypoxia. RESULTS: SKA3 was up-regulated in NGS, TCGA and GSE107943 databases and was associated with poor prognosis. Function...