Non‐SMC condensin I complex subunit H participates in anti‐programmed cell death‐1 resistance of clear cell renal cell carcinomas

• Published in: Cell proliferation Vol. 56; no. 7; pp. e13400 - n/a
• Main Authors: Chen, Zhi, Ruan, Weiqiang, Guo, Chunhao, Chen, Ke, Li, Le, Tian, Jihua, Hu, Zhiquan, Peng, Dan, Zeng, Xing
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.07.2023; John Wiley and Sons Inc
• Subjects: Antibodies; Apoptosis; Assaying; Breast cancer; Cancer; Cell cycle; Cell death; Cervical cancer; Clear cell-type renal cell carcinoma; Condensin; Enzymes; Flow cytometry; Foxp3 protein; Glycolysis; Immunological tolerance; Immunoprecipitation; Immunoregulation; Lung cancer; Lymphocytes; Lymphocytes T; Medical diagnosis; Medical prognosis; mRNA stability; N6-methyladenosine; Nuclear transport; Original; PD-L1 protein; Plasmids; Proteins; Regulatory mechanisms (biology); Therapeutic targets; Ubiquitination; β-Catenin
• ISSN: 0960-7722; 1365-2184
• DOI: 10.1111/cpr.13400

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. FOXP3‐mediated transcription and FUS‐mediated splicing increases MCAPH expression. YTHDC1 induces non‐SMC condensin I complex subunit H (NCAPH) mRNA nuclear export and IGF2BP3 enhances NCAPH mRNA stability in an m6A‐dependent manner. The elevated NCAPH proteins then enhance the stability of β‐catenin and activate β‐catenin‐related signalling pathway, which further promotes aerobic glycolysis and immune escape of clear cell renal cell carcinoma.