STAMBPL1 promotes triple-negative breast cancer angiogenesis by upregulating the transcription of GRHL3/HIF1α/VEGFA via FOXO1

Abstract Anti-angiogenesis is a crucial therapeutic strategy for triple-negative breast cancer (TNBC), but the current targeted drugs are insufficient to meet clinical requirements. Our study has discovered that silencing the deubiquitinating enzyme STAMBPL1 can effectively inhibit the growth and angiogenesis of TNBC xenografts in nude mice. STAMBPL1 promotes the expression of HIF1α/VEGFA in TNBC through a non-enzymatic-dependent mechanism. STAMBPL1 interacts with the transcription factor FOXO1, which binds to the promoter of the GRHL3 gene, thereby positively regulating its transcription. Subsequently, GRHL3 binds to the HIF1α gene promoter to promote its transcription and angiogenesis. Moreover, we have demonstrated that the combination of FOXO1 inhibitor AS1842856 and VEGFR inhibitor Apatinib significantly inhibited the growth of transplanted tumors in nude mice. These findings indicate that the STAMBPL1/FOXO1/GRHL3/HIF1α/VEGFA axis provides potential therapeutic targets in TNBC.