N6-Methyladenosine Modification of circIST1 Promotes Hypoxia-Inducible Factor α–mediated Glycolysis and Progression in Hepatocellular Carcinoma

Abstract

The involvement of circular RNAs (circRNAs) have been well-documented in various cancers, including hepatocellular carcinoma (HCC); however, their regulatory roles in HIF-1α-mediated tumorigenesis remain largely unclear. This study elucidates the functional significance of N6-methyladenosine (m6A)-modified circRNA—circIST1 in HCC progression. Elevated expression of circIST1 was observed in both HCC clinical specimens and cultured cell lines. This pronounced upregulation was found to be associated with poor prognosis and survival. Functionally, circIST1 drives HCC progression by enhancing tumor cell proliferation, migration, and invasion and by inhibiting apoptosis, as validated in vitro and in vivo. Mechanistically, it functions as a competitive endogenous RNA (ceRNA) that sponges miR-140-3p and miR-182, thereby relieving their repression on the common downstream oncogene, HIF-1α. Rescue experiments confirm that the tumor-suppressive effects of circIST1 silencing are reversed upon inhibition of these miRNAs or overexpression of HIF-1α. Notably, we show that circIST1 drives HIF-1α-mediated aerobic glycolysis—a metabolic hallmark of cancer—-by enhancing glucose uptake, lactate production, and glycolytic flux. Furthermore, we identify methyltransferase-like 3 (METTL3)-dependent m6A modification as a critical regulator of circIST1 stability. Collectively, our findings uncover a novel m6A-circIST1-miR-140-3p/miR-182-HIF-1α regulatory axis that underlies metabolic reprogramming in HCC, positioning circIST1 as a promising therapeutic target for HCC metabolic intervention.

Keywords

circIST1 / hepatocellular carcinoma / HIF-1α / m6A modification / microRNA sponge / tumor glycolysis

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