Loss of the tumor suppressor BTG3 drives a pro-angiogenic tumor microenvironment through HIF-1 activation

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.

Whole-genome mapping of APOBEC mutagenesis in metastatic urothelial carcinoma identifies driver hotspot mutations and a novel mutational signature

“…All other putative driver ApoHMs affected non-coding regions, including didymi in ADGRG6 , PLEKHS1 , TBC1D12 , and LEPROTL1 , proposed as drivers by other studies. 9 , 23 Other potential driver ApoHMs include RNF169 (involved in DNA damage repair), 24 BTG3 (angiogenesis), 25 ADM (adrenomedullin, a vasodilator), 26 GDF3 (regulation of transforming growth factor β [TGF-β]), 27 and WDR74 (ribosome biogenesis). 28 …”

Coordinated modulation of long non-coding RNA ASBEL and curcumin co-delivery through multicomponent nanocomplexes for synchronous triple-negative breast cancer theranostics

“…We and other groups have demonstrated that knockdown of lncRNA ASBEL could inhibit cell viability, migration/invasion and induce apoptosis in various types of cancer cells through upregulating BTG3 expression. Upregulation of BTG3 was closed linked to the tumorigenesis of various cancers [ 63 ]. Thus, the main goal of our current study is that whether targeted and combination modulation of lncRNA ASBEL/BTG3 with antago3 and Cur co-delivery by FCANPs would result in enhanced therapy efficiency in MDA-MB-231 cells due to their synergistic effects.…”

Whole-genome mapping of APOBEC mutagenesis in metastatic urothelial carcinoma identifies driver hotspot mutations and a novel mutational signature

“…All other putative driver ApoHM affected non-coding regions including didymi in ADGRG6 , PLEKHS1 , TBC1D12 and LEPROTL1 proposed as drivers by other studies 9,22 . Other potential driver ApoHM include RNF169 (involved in DNA damage repair) 23 , BTG3 (angiogenesis) 24 , ADM (adrenomedullin; vasodilator) 25 , GDF3 (regulation of TGF-beta) 26 and WDR74 (ribosome biogenesis) 27 .…”