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Updated: May 22, 2025

SUMO-Binding Entities SUBEs as Tools for the Enrichment, Isolation, Identification, and Characterization of the SUMO Proteome in Liver Cancer
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SUMO-Binding Entities SUBEs as Tools for the Enrichment, Isolation, Identification, and Characterization of the SUMO Proteome in Liver Cancer

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

Xia Zhang1, Zhenxuan Chen1, Xiaobo He1

  • 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|March 17, 2025
PubMed

Insights

Bladder cancer (BC) growth is promoted by SET-domain-containing protein 8 (SETD8), which stabilizes the MYC protein. Targeting the SETD8/MYC pathway with inhibitors like UNC0379 offers a promising therapeutic strategy for BC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Aberrant transcriptional and epigenetic regulation drives bladder cancer (BC) progression.
  • Identifying novel therapeutic targets in BC remains a critical unmet need.

Purpose of the Study:

  • To identify key transcriptional and epigenetic regulators of bladder tumor growth.
  • To investigate the role of SET-domain-containing protein 8 (SETD8) in BC pathogenesis.
  • To elucidate the mechanism by which SETD8 promotes BC and evaluate its therapeutic potential.

Main Methods:

  • CRISPR-Cas9 library screening targeting epigenetic factors.
  • Analysis of SETD8 and MYC protein expression in BC patient samples.
  • In vitro and in vivo studies assessing tumor growth inhibition.
  • Investigation of protein-protein interactions and post-translational modifications (methylation, SUMOylation).

Main Results:

  • SETD8 is overexpressed in BC and correlates with poor prognosis.
  • SETD8 directly methylates MYC at K412, disrupting CHIP interaction and stabilizing MYC.
  • SUMOylation of SETD8 further enhances MYC methylation and stability.
  • SETD8 inhibition (genetic or pharmacological with UNC0379) reduces MYC levels and suppresses BC growth in vitro and in vivo.

Conclusions:

  • The SETD8/MYC axis is a critical driver of bladder cancer.
  • SETD8 acts as an oncogene in BC by stabilizing MYC.
  • Targeting SETD8 represents a promising therapeutic strategy for bladder cancer patients.
Keywords:
MYCSETD8SUMOylationbladder cancer (BC)methylationtumor growth

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