SUMOylation of SETD8 Promotes Tumor Growth by Methylating and Stabilizing MYC in Bladder Cancer

Abstract Aberrant transcriptional and epigenetic landscape plays crucial roles in the progression of bladder cancer (BC). However, effective therapeutic targets derived from these processes remain undeveloped. This study pinpoints SET‐domain‐containing protein 8 (SETD8) as a pivotal gene that promotes bladder tumor growth through a screening with a CRISPR‐Cas9 library targeting transcriptional and epigenetic factors. BC patient samples display elevated SETD8 protein expression, and higher expression of SETD8 correlates with poorer prognosis. Further, MYC is identified as a novel substrate for SETD8. Specifically, SETD8 methylates MYC at lysine 412 (K412), disrupting the interaction between MYC and the E3 ubiquitin ligase CHIP, which results in MYC stabilization and ultimately promotes tumor growth both in vitro and in vivo. Moreover, this study uncovers that SUMOylation of SETD8 leads to SETD8 stabilization. The SUMOylated SETD8 further enhances MYC methylation and stabilization via SUMO‐SIM interaction. Knocking down SETD8 or using the SETD8 specific inhibitor UNC0379 substantially reduces the protein level of MYC and inhibits the bladder tumor growth in vitro and in vivo. These findings provide strong support for the idea that targeting the SETD8/MYC axis offers a promising therapeutic approach for BC patient.