PYCR1 通过 IRS1 的乳酰化修饰调控其表达促进肝癌细胞生长转移。
PYCR1 promotes liver cancer cell growth and metastasis by regulating IRS1 expression through lactylation modification.
机构信息
The Key Laboratory of Rare Metabolic Disease, Department of Biochemistry and Molecular Biology, The Key Laboratory of Human Functional Genomics of Jiangsu Province, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
出版信息
Clin Transl Med. 2024 Oct;14(10):e70045. doi: 10.1002/ctm2.70045.
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 demonstrating the potential of targeting PYCR1 to inhibit LC cell proliferation and metastasis, this study identified PYCR1 as a promising therapeutic target for LC.
HIGHLIGHTS
Pyrroline-5-carboxylate reductase 1 (PYCR1) promotes the proliferation and metastasis of liver cancer (LC) cells. The expression of PYCR1 in LC is regulated by DNA methylation. Knocking down or inhibiting PYCR1 inhibits glycolysis as well as the PI3K/AKT/mTOR and MAPK/ERK pathways in LC cells. PYCR1 regulates the transcriptional activity of IRS1 by affecting H3K18 lactylation in its promoter region.
背景
肝癌（LC）是全球最致命的癌症之一，现有治疗方法的疗效有限。本研究旨在阐明吡咯啉-5-羧酸还原酶 1（PYCR1）作为 LC 潜在治疗靶点的作用和潜在机制。
方法
免疫组织化学和 Western blot 用于分析 LC 细胞和组织中 PYCR1 的表达。EdU 测定、集落形成测定、划痕愈合测定、Transwell 测定、裸鼠异种移植模型和裸鼠肺转移模型用于检测 LC 细胞的生长和转移能力。转录组测序用于搜索受 PYCR1 调节的下游靶基因，代谢组学用于鉴定受 PYCR1 调节的下游代谢物。ChIP 测定用于分析 IRS1 启动子区域 H3K18 乳糖化的富集。
结果
我们发现 PYCR1 在 HCC 中的表达明显增加，并且这种高表达与 HCC 患者的预后不良相关。在体内和体外，敲除或抑制 PYCR1 均抑制 HCC 细胞的增殖、迁移和侵袭。此外，我们揭示了敲除或抑制 PYCR1 可以抑制 HCC 细胞中的糖酵解并减少 IRS1 组蛋白的 H3K18 乳糖化，从而抑制 IRS1 的表达。
结论
我们的研究结果确定 PYCR1 是 LC 进展的关键调节因子，影响肿瘤细胞的代谢和基因表达。通过证明靶向 PYCR1 抑制 LC 细胞增殖和转移的潜力，本研究确定 PYCR1 是 LC 的有前途的治疗靶点。
重点
吡咯啉-5-羧酸还原酶 1（PYCR1）促进肝癌（LC）细胞的增殖和转移。LC 中 PYCR1 的表达受 DNA 甲基化调控。敲低或抑制 PYCR1 可抑制 LC 细胞中的糖酵解以及 PI3K/AKT/mTOR 和 MAPK/ERK 通路。PYCR1 通过影响 IRS1 启动子区域的 H3K18 乳糖化来调节 IRS1 的转录活性。
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