PYCR1 promotes liver cancer cell growth and metastasis by regulating IRS1 expression through lactylation modification

作者：Haoyu Wang, Mu Xu, Tong Zhang, Jinkun Pan, C. Li, Bei Pan, Linpeng Zhou, Yun Huang, Chenzi Gao, Mengping He, Yao Xue, Xuetao Ji, Xu Zhang, Ning Wang, Hongwen Zhou, Qian Wang, John Li · 发表于：Clinical and Translational Medicine · 年份：2024 · DOI：10.1002/ctm2.70045 · 被引用次数：52 · 研究领域：Peptidase Inhibition and Analysis、Histone Deacetylase Inhibitors Research、Sirtuins and Resveratrol in Medicine

BACKGROUND: Liver cancer (LC) is among the deadliest cancers worldwide, with existing treatments showing limited efficacy. This study aimed to elucidate the role and underlying mechanisms of pyrroline-5-carboxylate reductase 1 (PYCR1) as a potential therapeutic target in LC. METHODS: Immunohistochemistry and Western blot were used to analyse the expression of PYCR1 in LC cells and tissues. EdU assays, colony-forming assays, scratch wound healing assays, Transwell assays, nude mouse xenograft models and nude mouse lung metastasis models were used to detect the growth and metastasis abilities of LC cells. Transcriptome sequencing was used to search for downstream target genes regulated by PYCR1, and metabolomics was used to identify the downstream metabolites regulated by PYCR1. ChIP assays were used to analyse the enrichment of H3K18 lactylation in the IRS1 promoter region. RESULTS: We found that the expression of PYCR1 was significantly increased in HCC and that this high expression was associated with poor prognosis in HCC patients. Knockout or inhibition of PYCR1 inhibited HCC cell proliferation, migration and invasion both in vivo and in vitro. In addition, we revealed that knocking out or inhibiting PYCR1 could inhibit glycolysis in HCC cells and reduce H3K18 lactylation of the IRS1 histone, thereby inhibiting IRS1 expression. CONCLUSIONS: Our findings identify PYCR1 as a pivotal regulator of LC progression that influences tumour cell metabolism and gene expression. By de...