Abstract
Diabetes is an important risk factor for liver cancer, but its mechanism is unknown. Corosolic acid (CA) has been proven to have both hypoglycemic and antitumor effects, so revealing the function of CA can help us understand the relationship between diabetes and liver cancer. In previous studies, we confirmed that CA can effectively inhibit the expression of YAP, an important oncoprotein in HCC cells, and the proliferation of HCC cells. In addition, we also found that O-GlcNAcylation plays an indispensable role in HCC tumorigenesis. However, it is not clear whether CA can inhibit the effect of O-GlcNAcylation on HCC cells. In this study, the antitumor ability of CA was investigated by inhibiting the O-GlcNAcylation level and its corresponding mechanism. The results showed that HG (high glucose) could promote the proliferation of liver cancer cells, while CA could inhibit cell growth under HG conditions and tumor growth in a xenotransplantation model. CA can inhibit the activation of the HBP pathway and reduce the expression of YAP and OGT under HG conditions. Importantly, we found that CA can reduce YAP expression and O-GlcNAcylation by inhibiting the activity of CDK19. Overexpression of CDK19 partially reversed the CA-induced decrease in YAP and O-GlcNAcylation. This is the first evidence that CA can reduce the proliferative capacity of cells with high glucose levels and further inhibit tumor growth by inactivating the CDK19/YAP/O-GlcNAcylation pathway, suggesting that CA is a candidate drug for the development of treatments against diabetes-associated liver cancer.
Highlights
Liver cancer is one of the most common malignancies worldwide; because of its high incidence and mortality, its etiology and pathogenesis have been a hot topic of discussion for many years [1]
We found that the levels of O-linked N-acetylglucosamine (GlcNAc) transferase (OGT), Yes-associated protein (YAP), and O-GlcNAcylation in liver cancer cells with cyclin-dependent kinase 19 (CDK19) knockout were increased compared to those treated with Corosolic acid (CA) alone, suggesting that CA downregulates global O-GlcNAcylation in liver cancer cells in a CDK19-dependent manner (Supplementary Fig. 6A–C)
We found that OGT, the only known endogenous enzyme that catalyzes OGlcNAcylation [30, 31], was significantly upregulated in liver cancer tissues compared to adjacent normal tissues
Summary
Liver cancer is one of the most common malignancies worldwide; because of its high incidence and mortality, its etiology and pathogenesis have been a hot topic of discussion for many years [1]. Diabetes-associated metabolic disorders have been widely recognized as one of the major risk factors for the occurrence and prognosis of liver cancer [2, 3], and the incidence and mortality of liver cancer in patients with diabetes are significantly increased [4, 5]. Hyperglycemia induces overactivity of the hexosylamine biosynthesis pathway (HBP), leading to increased synthesis of UDP-N-acetyl-D-glucosamine, a substrate that O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) uses to OGlcNAcylate the target protein [6]. We have previously reported that high glucose (HG)-linked increases in the OGlcNAcylation of target proteins plays significant roles in the development of liver cancer [11,12,13], HG is able to induce OGlcNAcylation and expression and Yes-associated protein (YAP) can be modified by O-GlcNAcylation to increase its stability. We found that YAP can positively regulate glucose uptake, the synthesis of metabolites used in the HBP, and cellular O-GlcNAcylation, establishing a positive feedback loop [13]
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