VGLL4 interacts with STAT3 to function as a tumor suppressor in triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is an aggressive malignancy with a poor prognosis, and there are no effective molecular-targeted drugs for TNBC patients in clinical practice. The JAK-STAT pathway is implicated in tumorigenesis and the progression of various cancers. In this study, the results demonstrated that VGLL4 is expressed at low levels in both TNBC specimens and cell lines and that VGLL4 expression is negatively correlated with Ki67 expression and tumor size in TNBC patients. VGLL4 knockdown can promote the growth of TNBC cells, while VGLL4 overexpression significantly suppresses the growth of TNBC cells in vitro. More importantly, VGLL4 significantly inhibits tumor progression in a nude mouse model. In addition, VGLL4 is a direct target of miR-454, and the upregulation of miR-454 decreases VGLL4 expression and promotes the cell growth of TNBC cells. Furthermore, we also demonstrated that VGLL4 interacts with STAT3, the core component of the JAK-STAT pathway, leading to the inactivation of STAT3 and the inhibition of STAT3 downstream transcription. Collectively, these findings indicate that VGLL4 expression is negatively associated with poor prognosis in TNBC patients. High expression of miR-454 may be one of the causes of the downregulation of VGLL4 in TNBC, and VGLL4 acts as a tumor suppressor in TNBC by interacting with STAT3 and subsequently suppresses the STAT3 signaling axis, providing potential biomarkers and therapeutic approaches for this fatal disease.

Critical role of VGLL4 in the regulation of chronic normobaric hypoxia‐induced pulmonary hypertension in mice

“…Interestingly, the increase in STAT3 expression was also seen in the immune‐complex precipitated by pan‐acetylated lysine, ac‐H3K9 and ac‐H3K27 antibodies, and was suppressed after resveratrol treatment, and STAT3 knock down alleviated CNH‐induced PH, indicating that abrogation of VGLL4 acetylation reversed CNH‐induced PH by attenuating STAT3 signaling. However, our results are contrary to those of a recent study conducted by Song et al 50 In that study, the authors reported that inhibiting VGLL4 elevated p‐STAT3 expression and conversely, VGLL4 over‐expression inhibited p‐STAT3 expression. These conflicting results may be due to the differences in the context of the models investigated (PH mice vs. breast cancer).…”

Maternal vgll4a promotes blastoderm cohesion enabling yap1-mediated mechano-transduction during zebrafish epiboly

“…Given that maternal vgll4a seemed to act upstream of yap1, we hypothesized that its activity could regulate blastomere adhesion and thus their tension probing capacity. Indeed, in cancer cells VGLL4 regulates the transcription of E-cadherin (Li et al , 2015; Song et al , 2019) and the E-cadherin/α-Catenin/β-Catenin adhesion complex is an upstream regulator of Yap1 in different biological contexts (Kim et al , 2011; Schlegelmilch et al , 2011; Silvis et al , 2011). Furthermore, the epibolic phenotype of MZvgll4a embryos resembled that of the pou5fl/Oct4 deficient MZspg embryos (Lachnit et al , 2008; Song et al , 2013).…”

Targeting regulated cell death (RCD) with small-molecule compounds in triple-negative breast cancer: a revisited perspective from molecular mechanisms to targeted therapies

“…CD44 + /CD24 − stem cell-like population in TNBC tended to be a more aggressive phenotype [ 277 – 281 ], and cancer stem cell (CSC) was resistant to anoikis by allowing replication independent of anchoring [ 282 , 283 ]. STAT3 could regulate stem cell self-renewal and differentiation and resist anoikis [ 284 , 285 ]. It was also overexpressed and structurally activated in TNBC cells.…”