CAPNS1/Dicer反馈环路通过抑制MicroRNA库成熟促进肝细胞癌糖酵解增殖和转移

Abstract

Hepatocellular carcinoma (HCC) is the common malignancy in digestive system, characterized by glucose metabolic reprogramming, which supplies the necessary nutrients and energy to sustain significantly increased cell proliferation and metastasis. However, the underlying mechanistic connections between glycolysis and HCC cells have not been comprehensively elucidated. Herein, through whole-gene CRISPR library screen, Calpain S1 (CAPNS1) was considered a key gene that significantly promotes cell proliferation under conditions where cells rely solely on glycolytic metabolism. Higher CAPNS1 levels were found in HCC tissues, correlating with increased glycolysis level, advanced tumor stage, and shorter survival days. CAPNS1 overexpression enhanced glycolysis, proliferation, and metastasis of HCC cells, whereas CAPNS1 knockdown produced inverse effects. CAPNS1 interacted with calpain 2 to form heterodimers, bound to Dicer, and cleaved Dicer at the arginine 1910 site, thereby suppressing the maturation of various microRNAs, such as miR-200a-3p and miR-122-5p, which targeting enzymes of glycolysis. The lactate produced from glycolysis increased H3K27 acetylation at the promoter region of CAPNS1, thereby enhancing CAPNS1 transcription. Taken together, the CAPNS1/Dicer feedback loop facilitated glycolysis, proliferation, and metastasis in HCC cell by inhibiting the maturation of the microRNA pool. Consequently, CAPNS1 may represent as a remarkable biomarker and therapic target for HCC.