Dataset Information

FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to the HIF2α blockade by facilitating LDHA phosphorylation.

ABSTRACT: Renal cell carcinoma (RCC) is one of the three major malignant tumors of the urinary system and originates from proximal tubular epithelial cells. Clear cell renal cell carcinoma (ccRCC) accounts for approximately 80% of RCC cases and is recognized as a metabolic disease driven by genetic mutations and epigenetic alterations. Through bioinformatic analysis, we found that FK506 binding protein 10 (FKBP10) may play an essential role in hypoxia and glycolysis pathways in ccRCC progression. Functionally, FKBP10 promotes the proliferation and metastasis of ccRCC in vivo and in vitro depending on its peptidyl-prolyl cis-trans isomerase (PPIase) domains. Mechanistically, FKBP10 binds directly to lactate dehydrogenase A (LDHA) through its C-terminal region, the key regulator of glycolysis, and enhances the LDHA-Y10 phosphorylation, which results in a hyperactive Warburg effect and the accumulation of histone lactylation. Moreover, HIFα negatively regulates the expression of FKBP10, and inhibition of FKBP10 enhances the antitumor effect of the HIF2α inhibitor PT2385. Therefore, our study demonstrates that FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to HIF2α blockade by facilitating LDHA phosphorylation, which may be exploited for anticancer therapy.

SUBMITTER: Liu R

PROVIDER: S-EPMC10794466 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to the HIF2α blockade by facilitating LDHA phosphorylation.

Liu Ren R Zou Zhihao Z Chen Lingwu L Feng Yuanfa Y Ye Jianheng J Deng Yulin Y Zhu Xuejin X Zhang Yixun Y Lin Jundong J Cai Shanghua S Tang Zhenfeng Z Liang Yingke Y Lu Jianming J Zhuo Yangjia Y Han Zhaodong Z Ling Xiaohui X Liang Yuxiang Y Wang Zongren Z Zhong Weide W

Cell death & disease 20240117 1

Renal cell carcinoma (RCC) is one of the three major malignant tumors of the urinary system and originates from proximal tubular epithelial cells. Clear cell renal cell carcinoma (ccRCC) accounts for approximately 80% of RCC cases and is recognized as a metabolic disease driven by genetic mutations and epigenetic alterations. Through bioinformatic analysis, we found that FK506 binding protein 10 (FKBP10) may play an essential role in hypoxia and glycolysis pathways in ccRCC progression. Function ...[more]

PMID: 38233415

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Project description:Clear cell renal cell carcinoma (ccRCC), the most common urological malignancy, has an unfavorable prognosis and an unknown mechanism of progression. Through survival analyses screening of The Cancer Genome Atlas (TCGA) dataset, we identified Visual system homeobox1 (VSX1) as a novel potential prognostic biomarker in ccRCC and subsequently investigated the oncogenic role of VSX1 in ccRCC. The differential expression of VSX1 in human tumors and the clinical prognoses were analyzed in the TCGA dataset and Gene Expression Omnibus. Spearman's correlation coefficient was determined for the correlation analysis of VSX1 expression and other genes of interest. The roles of VSX1 in cell proliferation, invasion, and migration of ccRCC cells were evaluated via the CCK-8 assay, colony formation assay, and Transwell assay, respectively. Further results were demonstrated by western blotting, immunohistochemistry, qRT-PCR, tumor sphere formation, flow cytometry, and the dual‑luciferase reporter assay. VSX1 mRNA upregulation was generally observed in multiple human malignancies from the TCGA database and was confirmed in ccRCC clinical specimens from our department. High VSX1 expression usually indicated that overall and disease-free survival were unfavorable for patients with ccRCC. In terms of mechanism, knockdown or overexpression of VSX1 affected ccRCC aggressiveness in vitro. The dual-luciferase reporter gene assay implied that VSX1 overexpression significantly increased the luciferase activity of TMEM44, FKBP10, and TRIB3, which indicated that VSX1 promoted ccRCC invasiveness via transcriptional regulation of these genes. The significantly enhanced growth in vitro that was induced by stable VSX1 overexpression was almost restored to normal by the knockdown of FKBP10. This study demonstrated that VSX1 was a novel prognostic biomarker in ccRCC and that high VSX1 expression promoted cell proliferation, invasion, and migration in ccRCC via transcriptional activation of downstream target genes.

Dataset Information

FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to the HIF2α blockade by facilitating LDHA phosphorylation.

Publications

FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to the HIF2α blockade by facilitating LDHA phosphorylation.

Similar Datasets

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