Monomethyltransferase SET8 facilitates hepatocellular carcinoma growth by enhancing aerobic glycolysis

Abstract

Hepatocellular carcinoma (HCC) is one of the most aggressive cancers worldwide. Despite such a public health importance, efficient therapeutic agents are still lacking for this malignancy. Most tumor cells use aerobic glycolysis to sustain anabolic growth, including HCC, and the preference of glycolysis often leads to a close association with poorer clinical outcomes. The histone methyltransferase SET8 plays crucial roles in controlling cell-cycle progression, transcription regulation, and tumorigenesis. However, it remains largely undefined whether SET8 affects the glucose metabolism in HCC. Here, we report that upregulation of SET8 is positively correlated with a poor survival rate in HCC patients. Both in vitro and in vivo studies revealed that SET8 deficiency conferred an impaired glucose metabolism phenotype and thus inhibited the progression of HCC tumors. By contrast, SET8 overexpression aggravated the glycolytic alterations and tumor progression. Mechanistically, SET8 directly binds to and inactivates KLF4, resulting in suppression of its downstream SIRT4. We also provided further evidence that mutations in SET8 failed to restrain the transactivation of SIRT4 by KLF4. Our data collectively uncover a novel mechanism of SET8 in mediating glycolytic metabolism in HCC cells and may provide a basis for targeting SET8 as a therapeutic strategy in HCC.

High Glucose Induces Endothelial COX2 and iNOS Expression via Inhibition of Monomethyltransferase SETD8 Expression

“…SET domain-containing protein 8 (SETD8), also known as SET8, is the only known lysine methyltransferase responsible for specific monomethylation on histone H4 at lysine 20 (H4K20me1) [12]. The methyltransferase activity of SETD8 is involved in a variety of crucial cellular functions, including DNA repair, cell cycle progression, transcriptional and posttranslational regulation, and cellular metabolism [12,13]. We previously indicated that SETD8 downregulation is involved in high glucose-mediated endothelial inflammation in HUVECs [14].…”

MiRNA-340-5p Mediates the Functional and Infiltrative Promotion of Tumor-Infiltrating CD8+ T Lymphocytes in Human Diffuse Large B Cell Lymphoma

“…However, rather than a ubiquitination enzyme, KMT5A was the only known speci c lysine methyltransferase that monomethylates histone H4 at lysine 20 (H4K20me1) (25). The methyltransferase activity of KMT5A plays crucial roles in various cell biological processes, including transcriptional regulation and cell metabolism (26). Therefore, our results indicated that ubiquitination enzymes were involved in KMT5A-regulation of CD73.…”

MiRNA-340-5p mediates the functional and infiltrative promotion of tumor-infiltrating CD8+ T lymphocytes in human diffuse large B cell lymphoma

“…However, rather than a ubiquitination enzyme, KMT5A is the only known speci c lysine methyltransferase that monomethylates histone H4 at lysine 20 (H4K20me1) (32). The methyltransferase activity of KMT5A plays crucial roles in various cell biological processes, including transcriptional regulation and cell metabolism (33). Therefore, our results indicated that ubiquitination enzymes were involved in the KMT5A-mediated regulation of CD73.…”