Abstract
Non-SMC condensin I complex subunit H (NCAPH) is reported to play an important role and be a poor prognostic factor in various cancers. However, the function and regulatory mechanism of NCAPH in clear cell renal cell carcinoma (ccRCC) remain unknown. The roles of NCAPH on ccRCC growth were detected in vitro and in vivo assays. The regulatory mechanism of NCAPH was explored by immunoprecipitation assay, ubiquitination assay, ChIP assay, RIP assay, luciferase reporter assay and RNA pull-down assay. The role of NCAPH in immunoregulation also was explored by flow cytometry, T cell-mediated tumour cell killing assay and immune-competent mouse model. In this research, we displayed that NCAPH was upregulated in ccRCC and patients with elevated NCAPH expression had an undesirable prognosis. Functionally, NCAPH depletion restrained ccRCC growth in vitro and in vivo. The elevated NCAPH was attributed to FOXP3-mediated transcription, FUS-mediated transcription splicing and METTL3-mediated m6A modification. Moreover, YTHDC1 promoted NCAPH mRNA nuclear export, and IGF2BP3 enhanced NCAPH mRNA stability in an m6A-dependent manner. NCAPH increased PD-L1 expression by inhibiting the degradation of β-catenin in ccRCC cells, which further facilitated aerobic glycolysis and immune tolerance of ccRCC. Collectively, our findings display the vital function of NCAPH in ccRCC and uncover that NCAPH may be regarded as a potential therapeutic target to reverse the immune tolerance of ccRCC.