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BEX4 inhibits the progression of clear cell renal cell carcinoma by stabilizing SH2D4A, which is achieved by blocking

Ziyao Li1,2,3, Shiyong Xin4, Liqun Huang1

  • 1Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.

Oncogene
|December 5, 2024
PubMed

Insights

Brain-expressed X-linked 4 (BEX4) inhibits clear cell renal cell carcinoma (ccRCC) progression by downregulating the NOTCH pathway via SH2D4A stabilization. Low BEX4 expression correlates with poor ccRCC prognosis, suggesting BEX4 as a potential therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Clear cell renal cell carcinoma (ccRCC) is a prevalent malignancy.
  • Brain-expressed X-linked 4 (BEX4) has emerged as a gene of interest in cancer progression.
  • Understanding BEX4's role in ccRCC is crucial for developing new therapeutic strategies.

Purpose of the Study:

  • To investigate the function of BEX4 in ccRCC.
  • To elucidate the underlying molecular mechanisms of BEX4's action in ccRCC.
  • To evaluate BEX4 as a potential diagnostic and therapeutic target for ccRCC.

Main Methods:

  • Bioinformatics analysis to assess BEX4 expression in ccRCC tissues.
  • In vitro cell function assays to evaluate ccRCC cell proliferation.
  • In vivo nude mouse xenograft model to assess tumorigenesis.
  • Molecular assays to investigate BEX4's regulatory effects on SH2D4A, SIRT2, and the NOTCH pathway.
  • Dual-luciferase assays to assess the regulation of BEX4 transcriptional activity by ATF3.

Main Results:

  • BEX4 was significantly downregulated in ccRCC, with lower expression correlating with poorer overall survival.
  • BEX4 inhibited ccRCC cell proliferation in vitro and tumorigenesis in vivo.
  • BEX4 positively regulated SH2D4A expression by inhibiting SIRT2 activity, leading to increased acetylation and stabilization of SH2D4A at the K69 site.
  • BEX4's tumor-suppressive effects were mediated through the inhibition of the NOTCH pathway via SH2D4A.
  • Activation transcription factor 3 (ATF3) positively regulated BEX4 transcriptional activity.

Conclusions:

  • BEX4 functions as a tumor suppressor in ccRCC.
  • BEX4 inhibits ccRCC progression by stabilizing SH2D4A, downregulating the NOTCH pathway.
  • BEX4 represents a promising novel diagnostic and therapeutic target for ccRCC.

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