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Silent information regulator 2 promotes clear cell renal cell carcinoma progression through deacetylation and small ubiquitin-related modifier 1 modification of glucose 6-phosphate dehydrogenase.

ABSTRACT: The regulatory relationship between silent information regulator 2 (SIRT2) and glucose 6-phosphate dehydrogenase (G6PD) in clear cell renal cell carcinoma (ccRCC) is still unclear. The present study aimed to explore the function of SIRT2 and its regulatory effect on G6PD in ccRCC. The Cancer Genome Atlas data mining of SIRT2 was first analyzed. Quantitative real-time PCR and western blot analyses were used to assess the mRNA and protein expression levels, respectively. Cell viability, colony formation, cell cycle, cell apoptosis, and TUNEL assays and EdU staining were used to investigate the roles of SIRT2 in ccRCC proliferation and apoptosis. The coimmunoprecipitation (Co-IP) assay was used to analyze the association between SIRT2 and G6PD in ccRCC cells. Quantitative Co-IP assay was used to detect the levels of G6PD ubiquitination and small ubiquitin-related modifier 1 (SUMO1). An in vivo experiment was also carried out to confirm in vitro findings. The results indicated that SIRT2 promoted ccRCC proliferation and inhibited apoptosis by regulating cell cycle and apoptosis related proteins. Silent information regulator 2 interacted with G6PD, facilitated its activity through deacetylation, and increased its stability by reducing its ubiquitination and enhancing its SUMO1 modification. Silent information regulator 2 also promoted ccRCC tumor development in vivo. Taken together, the present study indicated that SIRT2 promoted ccRCC progression by increasing G6PD activity and stability, and it could be a potential new diagnostic and therapeutic target for ccRCC.

SUBMITTER: Ni Y

PROVIDER: S-EPMC8486209 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Ubiquitin modification is the most common protein post-translational modification (PTM) process in organisms, and 1332 ubiquitin regulators have been identified in humans. Ubiquitin regulators, especially E3 ligases and deubiquitinases, are widely involved in immune processes. This study aims to explore the ubiquitin modification features of clear cell renal cell carcinoma (ccRCC) and to elucidate the role of such ubiquitin modifications in shaping anti-tumor immunity and individual benefits from immune checkpoint blockade (ICB). A comprehensive analysis was performed in the TCGA cohort (n = 530) and GEO cohort (n = 682). RNA sequencing data of 758 differentially expressed regulators, which was validated by the proteomics data, was used for k-means unsupervised consensus clustering and three ubiquitin patterns of ccRCC were identified. Then, we focused on the ubiquitin modification and tumor progression signatures, immune infiltration characteristics, and prognostic value. The three patterns with different ubiquitin modification signatures correspond to "immune desert phenotype," "immune resistance phenotype," and "immune-inflammatory phenotype," respectively. To facilitate clinical application, we constructed a ubiquitin score to evaluate individual patients' ubiquitination outcome, and it was demonstrated to be an independent risk factor for overall survival (OS) in multivariate Cox analysis. It was found that the high score group was correlated to higher immune cells infiltrating level and PD-1/PD-L1/CTLA-4 expression. More importantly, we found that the high score group was predicted to be sensitive to anti-PD-1 treatment, while the low-score group showed lower predicted IC50 values in treatment with Pazopanib and Axitinib. In summary, this study elucidated the potential link between ubiquitin modification and immune infiltration landscape of ccRCC for the first time and provided a new assessment protocol for the precise selection of treatment strategies for patients with advanced ccRCC.

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Silent information regulator 2 promotes clear cell renal cell carcinoma progression through deacetylation and small ubiquitin-related modifier 1 modification of glucose 6-phosphate dehydrogenase.

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