Cbx4 Governs HIF-1α to Potentiate Angiogenesis of Hepatocellular Carcinoma by Its SUMO E3 Ligase Activity

Abstract

Cbx4 is a polycomb group protein that is also a SUMO E3 ligase, but its potential roles in tumorigenesis remain to be explored. Here, we report that Cbx4, but not other members of the Cbx family, enhances hypoxia-induced vascular endothelial growth factor (VEGF) expression and angiogenesis in hepatocellular carcinoma (HCC) cells through enhancing HIF-1α sumoylations at K391 and K477 in its two SUMO-interacting motifs-dependent mechanisms and increasing transcriptional activity of HIF-1. The Cbx4 expression is significantly correlated with VEGF expression, angiogenesis, and the overall survival of HCC patients and also in subcutaneously and orthotopically transplanted mice HCC models. Collectively, our findings demonstrate that Cbx4 plays a critical role in tumor angiogenesis by governing HIF-1α protein.

Context-dependent actions of Polycomb repressors in cancer

“…146 In addition, CBX4 promotes angiogenesis by its SUMO E3 ligase activity, an enzymatic ability that is unique among Pc-CBX proteins. 147,148 CBX8 was demonstrated to repress genes necessary for leukemic transformation, which is counteracted by the MLL-ENL fusion oncoprotein in MLL leukemia. 149 In contrast, CBX8 acts as an oncoprotein in breast cancer cell lines by interacting with SIRT1 and inhibiting Tp53 activity.…”

Cbx7 is epigenetically silenced in glioblastoma and inhibits cell migration by targeting YAP/TAZ-dependent transcription

“…This sequential feat by PRC2 followed by PRC1 induces further chromatin remodelling and ultimately transcriptional shut down of the locus. One of the important components of the PRC1 is the polycomb protein (Pc) known as chromobox protein in humans and other mammals7. Chromobox (Cbx) proteins are called so, owing to the presence of chromodomain motif ( chromatin organisation modifier ) in their structure.…”

“…Chromobox (Cbx) proteins are called so, owing to the presence of chromodomain motif ( chromatin organisation modifier ) in their structure. There are five chromobox proteins in humans, Cbx2, 4, 6, 7 and 8 and the pattern of their expression varies spatio-temporally7. Like other members of the PRC1 and PRC2 complexes, a number of studies and approaches have unveiled the role of Cbx proteins in tumorigenesis.…”

“…Like other members of the PRC1 and PRC2 complexes, a number of studies and approaches have unveiled the role of Cbx proteins in tumorigenesis. For instance, Cbx4 plays a crucial role in hepatocellular carcinoma by potentiating HIF1-alpha and bolstering the expression of VEGF7. Cbx8 knock-down exerts a paradoxical role in the progression of colorectal cancer by inhibiting proliferation while stimulating metastasis by enhancing migration and invasion capacities of tumour cells8.…”

Cbx4 Sumoylates Prdm16 to Regulate Adipose Tissue Thermogenesis

“…To determine which domain is required for Prdm16 stabilization, we generated mutants harboring SIM deletions or double point mutations at chromodomain (F11A/W35L). The F11A/W35L mutant has been shown to lose its binding to H3K27me3 and, thus, its polycomb-dependent function (Li et al, 2014). The mutants were transfected along with Prdm16 plasmids into HEK293 cells.…”