Identification of HDAC10 as a candidate oncogene in clear cell renal carcinoma that facilitates tumor proliferation and metastasis.

Abstract

Background: Clear cell renal cell carcinoma (ccRCC) remains one of the most lethal urological malignancies even though a great number of improvements in diagnosis and management have achieved over the past few decades. Accumulated evidence revealed that histone deacetylases (HDACs) play vital role in cell proliferation, differentiation and apoptosis. Nevertheless, the biological functions of histone deacetylation modification related genes in ccRCC remains poorly understood.

Method: Bulk transcriptomic data and clinical information of ccRCC patients were obtained from the TCGA database and collected from the Chinese PLA General Hospital. A total of 36 histone deacetylation genes were selected and studied in our research. Univariate cox regression analysis, least absolute shrinkage and selection operator (LASSO) regression, random forest (RF) analysis, and protein-protein interaction (PPI) network analysis were applied to identify key genes affecting the prognosis of ccRCC. The 'oncoPredict' algorithm was utilized for drug-sensitive analysis. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to explore the potential biological function. The ssGSEA algorithm was used for tumor immune microenvironment analysis. The expression levels of HDAC10 were validated by RT-PCR and immunohistochemistry (IHC). 5-ethynyl-2'-deoxyuridine (EdU assay), CCK-8 assay, cell transwell migration and invasion assay and colony formation assay were performed to detect the proliferation and invasion ability of ccRCC cells. A nomogram incorporating HDAC10 and clinicopathological characteristics was established to predict the prognosis of ccRCC patients.

Result: Two machine learning algorithms and PPI analysis identified four histone deacetylation genes that have a significant association with the prognosis of ccRCC, with HDAC10 being the key gene among them. HDAC10 is highly expressed in ccRCC and its high expression is associated with poor prognosis for ccRCC patients. Pathway enrichment and the experiments of EdU staining, CCK-8 assay, cell transwell migration and invasion assay and colony formation assay demonstrated that HDAC10 mediated the proliferation and metastasis of ccRCC cells and involved in reshaping the tumor microenvironment (TME) of ccRCC. A clinically reliable prognostic predictive model was established by incorporating HDAC10 and other clinicopathological characteristics ( https://nomogramhdac10.shinyapps.io/HDAC10_Nomogram/ ).

Conclusion: Our study found the increased expression of HDAC10 was closely associated with poor prognosis of ccRCC patients. HDAC10 showed a pro-tumorigenic effect on ccRCC and promote the proliferation and metastasis of ccRCC, which may provide new light on targeted therapy for ccRCC.