Sodium butyrate blocks the growth of colorectal cancer by inhibiting the aerobic glycolysis mediated by SIRT4/HIF-1α

• Published in: Chemico-biological interactions 2024-11, Vol.403, p.111227, Article 111227
• Main Authors: Zhang, Qiuyu, Qin, Yong, Sun, Xiaodie, Bian, Zhongbo, Liu, Lulin, Liu, Huahuan, Mao, Lianzhi, Sun, Suxia
• Format: Article
• Language: English
• Subjects: Autophagy; Colorectal cancer; Glycolysis; SIRT4/HIF-1α; Sodium butyrate
• ISSN: 0009-2797; 1872-7786; 1872-7786
• DOI: 10.1016/j.cbi.2024.111227

The prevalence and mortality rates of colorectal cancer have been increasing in recent years, driven in part by the reliance of cancerous cells on aerobic glycolysis for growth. Sodium butyrate (NaB) has been shown to impede this process in colorectal cancer cells, although its mechanism of action remains unclear. In this study, we used cobalt chloride (CoCl2) to simulate a hypoxic environment and demonstrated that NaB downregulated hypoxia-inducible factor-1α (HIF-1α) protein levels under both normoxic and hypoxic conditions. By employing cycloheximide (CHX), MG132, and chloroquine (CQ), we investigated whether NaB affects HIF-1α protein levels via the autophagy pathway. Importantly, siRNA-mediated SIRT4 knockdown revealed that NaB promotes HIF-1α autophagic degradation by upregulating SIRT4 expression. This subsequently inhibits HIF-1α-mediated expression of GLUT1 and LDHA, reducing glucose uptake, lactate production, and ATP generation, ultimately suppressing aerobic glycolysis and cell proliferation in colorectal cancer cells. Furthermore, a human colorectal cancer xenograft model confirmed that butyric acid inhibited tumor growth in vivo, correlating with SIRT4 and HIF-1α modulation. In conclusion, our findings indicate that NaB hinders colorectal cancer progression by disrupting aerobic glycolysis mediated by SIRT4/HIF-1α. •NaB blocks the growth of colorectal cancer by inhibiting the aerobic glycolysis mediated by SIRT4/HIF-1α.•SIRT4 and HIF-1α participate in the antitumor effect of butyric acid in vivo.•NaB promotes HIF-1α degradation through the autophagy pathway by up-regulating SIRT4.