Insights into the Regulatory Roles of E3 Ubiquitin Ligases Associated with VHL-HIF Axis in Clear Cell Renal Cell Carcinoma

Abstract

Renal cell carcinoma (RCC) accounts for up to 85% to 90% of all kidney cancers. Clear cell RCC (ccRCC), the major subtype of RCC, is mainly characterized by the inactivation of the tumor suppressor gene VHL. pVHL as an E3 ubiquitin ligase targets the hydroxylated form of HIF-α for proteasomal degradation. The loss of VHL function leads to HIF-α aggregation as the main mechanism of ccRCC. Recently, the regulations of ccRCC through other E3 ubiquitin ligases are emerging. Moreover, most of them are associated with the VHL-HIF axis. In this review, we mainly focus on seven E3 ubiquitin ligases JADE1, SIAH1, CHIP, FBXW7, MDM2, SPOP, and HAF. Based on reported researches of these ligases on ccRCC, they are divided into two groups: JADE1, SIAH1, CHIP, and FBXW7 that negatively regulate the growth of ccRCC; MDM2, SPOP, and HAF that promote ccRCC progression. In addition, we further verify these possible links between these E3 ligases and VHL-HIF axis in ccRCC based on The Cancer Genome Atlas RNA-seq and Clinical data. Understanding the mechanisms by which these ligases regulate ccRCC, especially the interplay between these ligases and VHL-HIF axis may enable the development of novel therapeutic approaches for ccRCC. Overall, the present review reveals the potential mechanism by which seven ligases (JADE1, SIAH1, CHIP, FBXW7, MDM2, SPOP, and HAF) regulate ccRCC progression in detail, especially their relationship to VHL-HIF axis.