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Published on: July 20, 2019
Loss of the tumor suppressor BTG3 drives a pro-angiogenic tumor microenvironment through HIF-1 activation
Yu-Che Cheng1, Hsin-Yi Chiang1, Shang-Jung Cheng1
1Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Road, Taipei, 115, Taiwan.
Abstract:
B-cell translocation gene 3 (BTG3) is a member of the antiproliferative BTG gene family and is a downstream target of p53. Here, we show that senescence triggered by BTG3 depletion was accompanied by a secretome enriched with cytokines, growth factors, and matrix-remodeling enzymes, which could promote angiogenesis and cell scattering in vitro. We present evidence that at least part of these activities can be explained by elevated HIF-1α activity. Mechanistically, the BTG3 C-terminal domain competes with the coactivator p300 for binding the HIF-1α transactivation domain. The angiogenic promoting effect of BTG3 knockdown was largely diminished upon co-depletion of HIF-1α, indicating that HIF-1α is a major downstream target of BTG3 in the control of angiogenesis. In vivo, ectopic expression of BTG3 suppresses angiogenesis in xenograft tumors; and syngenic tumor growth and metastasis were enhanced in Btg3-null mice. Moreover, analysis of clinical datasets revealed that a higher BTG3/VEGFA expression ratio correlates with improved patient survival in a number of cancer types. Taken together, our findings highlight the non-autonomous regulation of tumor microenvironment by BTG3 while suppressing tumor progression.
Insights
B-cell translocation gene 3 (BTG3) depletion triggers senescence and promotes tumor growth by increasing angiogenesis via HIF-1α. Higher BTG3/VEGFA ratios correlate with better patient survival, suggesting BTG3 suppresses tumor progression.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- B-cell translocation gene 3 (BTG3) is an antiproliferative gene and a p53 target.
- BTG3's role in tumor microenvironment regulation and angiogenesis is not fully understood.
Purpose of the Study:
- To investigate the role of BTG3 in regulating senescence, angiogenesis, and tumor progression.
- To elucidate the molecular mechanisms linking BTG3, HIF-1α, and tumor microenvironment.
Main Methods:
- BTG3 depletion in cell cultures to analyze secretome changes and senescence.
- In vitro and in vivo assays using xenograft and syngenic tumor models.
- Analysis of clinical datasets to correlate BTG3/VEGFA expression with patient survival.
Main Results:
- BTG3 depletion induced senescence with a secretome promoting angiogenesis and cell scattering, mediated by elevated HIF-1α activity.
- BTG3 C-terminal domain competes with p300 for HIF-1α binding, with HIF-1α being a key downstream target in BTG3's control of angiogenesis.
- Ectopic BTG3 suppressed angiogenesis in vivo, while Btg3-null mice showed enhanced tumor growth and metastasis.
- A higher BTG3/VEGFA expression ratio correlated with improved patient survival across multiple cancer types.
Conclusions:
- BTG3 plays a crucial role in suppressing tumor progression by regulating the tumor microenvironment and angiogenesis.
- BTG3 exerts its anti-tumorigenic effects through the modulation of HIF-1α activity.
- BTG3 serves as a potential prognostic biomarker and therapeutic target in cancer.
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