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

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Clinical and Translational Medicine Pub Date : 2024-10-18 DOI:10.1002/ctm2.70045

Haoyu Wang, Mu Xu, Tong Zhang, Jinkun Pan, Chaopu Li, Bei Pan, Linpeng Zhou, Yun Huang, Chenzi Gao, Mengping He, Yao Xue, Xuetao Ji, Xu Zhang, Ning Wang, Hongwen Zhou, Qian Wang, John Zhong Li

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Abstract

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.

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PYCR1通过乳化修饰调节IRS1的表达，促进肝癌细胞的生长和转移

背景肝癌是全球致死率最高的癌症之一，现有的治疗方法疗效有限。本研究旨在阐明吡咯啉-5-羧酸还原酶 1（PYCR1）作为肝癌潜在治疗靶点的作用和内在机制。方法采用免疫组化和 Western 印迹法分析PYCR1 在 LC 细胞和组织中的表达。采用 EdU 试验、集落形成试验、划痕伤口愈合试验、Transwell 试验、裸鼠异种移植模型和裸鼠肺转移模型检测 LC 细胞的生长和转移能力。转录组测序用于寻找受PYCR1调控的下游靶基因，代谢组学用于鉴定受PYCR1调控的下游代谢产物。利用 ChIP 检测分析了 IRS1 启动子区域中 H3K18 乳化的富集情况。结果我们发现PYCR1在HCC中的表达明显增加，而且这种高表达与HCC患者的不良预后有关。敲除或抑制PYCR1可抑制HCC细胞在体内和体外的增殖、迁移和侵袭。此外，我们还发现敲除或抑制PYCR1可抑制HCC细胞的糖酵解，减少IRS1组蛋白的H3K18乳酰化，从而抑制IRS1的表达。结论我们的研究结果表明，PYCR1 是影响肿瘤细胞代谢和基因表达的 LC 进展的关键调节因子。通过证明靶向PYCR1抑制LC细胞增殖和转移的潜力，本研究发现PYCR1是治疗LC的一个有前景的靶点。研究亮点：吡咯啉-5-羧酸还原酶1（PYCR1）促进肝癌细胞的增殖和转移。 PYCR1在肝癌中的表达受DNA甲基化调控。敲除或抑制PYCR1可抑制肝癌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乳酰化来调节IRS1的转录活性。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.