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STAMBPL1 activates the GRHL3/HIF1A/VEGFA axis through interaction with FOXO1 to promote angiogenesis in

Huan Fang1,2, Huichun Liang1, Chuanyu Yang1

  • 1Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.

Elife
|April 10, 2025
PubMed

Insights

The deubiquitinase STAMBPL1 promotes triple-negative breast cancer angiogenesis by upregulating hypoxia-inducible factor 1-alpha (HIF1α) via the GRHL3 transcription factor. This pathway offers new therapeutic targets for advanced breast cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Anti-tumor angiogenesis is a key strategy for treating advanced and metastatic breast cancer.
  • The deubiquitinase STAMBPL1 was previously shown to enhance MKP-1 stability, contributing to cisplatin resistance in breast cancer.

Purpose of the Study:

  • To investigate the role of STAMBPL1 in promoting tumor angiogenesis in breast cancer.
  • To elucidate the molecular mechanism by which STAMBPL1 influences angiogenesis, particularly in triple-negative breast cancer.

Main Methods:

  • Investigated STAMBPL1's effect on hypoxia-inducible factor 1-alpha (HIF1α) expression in breast cancer cells.
  • Analyzed STAMBPL1-mediated HIF1A transcription and its impact on the HIF1α/VEGFA signaling pathway.
  • Utilized RNA-sequencing (RNA-seq) to identify downstream targets of STAMBPL1.
  • Examined the interaction between STAMBPL1, GRHL3, and FOXO1 in regulating gene transcription.

Main Results:

  • STAMBPL1 upregulates HIF1α expression in breast cancer cells through non-enzymatic transcription of HIF1A.
  • STAMBPL1 activates the HIF1α/VEGFA signaling pathway, promoting angiogenesis in triple-negative breast cancer.
  • GRHL3 was identified as a key downstream transcription factor mediating STAMBPL1-induced HIF1A transcription.
  • STAMBPL1 regulates GRHL3 transcription via interaction with the transcription factor FOXO1.

Conclusions:

  • STAMBPL1 plays a significant role in promoting breast cancer angiogenesis by modulating the HIF1α/VEGFA pathway.
  • The STAMBPL1/GRHL3/FOXO1 axis represents a novel mechanism in breast cancer pathogenesis.
  • These findings identify STAMBPL1 as a potential therapeutic target for treating triple-negative and advanced breast cancer.
Keywords:
FOXO1GRHL3HIF1αSTAMBPL1cancer biologyhumantriple-negative breast cancertumor angiogenesis

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