RNA‐binding protein SAMD4A inhibits breast tumor angiogenesis by modulating the balance of angiogenesis program

Abstract

Tumor‐induced angiogenesis is important for further progression of solid tumors. The initiation of tumor angiogenesis is dictated by a shift in the balance between proangiogenic and antiangiogenic gene expression programs. However, the potential mechanism controlling the expression of angiogenesis‐related genes in the tumor cells, especially the process mediated by RNA‐binding protein (RBP) remains unclear. SAMD4A is a conserved RBP across fly to mammals, and is believed to play an important role in controlling gene translation and stability. In this study, we identified the potential role of SAMD4A in modulating angiogenesis‐related gene expression and tumor progression in breast cancer. SAMD4A expression was repressed in breast cancer tissues and cells and low SAMD4A expression in human breast tumor samples was strongly associated with poor survival of patients. Overexpression of SAMD4A inhibited breast tumor angiogenesis and caner progression, whereas knockdown of SAMD4A demonstrated a reversed effect. Mechanistically, SAMD4A was found to specifically destabilize the proangiogenic gene transcripts, including C‐X‐C motif chemokine ligand 5 (CXCL5), endoglin (ENG), interleukin 1β (IL1β), and angiopoietin 1 (ANGPT1), by directly interacting with the stem‐loop structure in the 3′ untranslated region (3′UTR) of these mRNAs through its sterile alpha motif (SAM) domain, resulting in the imbalance of angiogenic genes expression. Collectively, our results suggest that SAMD4A is a novel breast tumor suppressor that inhibits tumor angiogenesis by specifically downregulating the expression of proangiogenic genes, which might be a potential antiangiogenic target for breast cancer therapy.

The Estrogen Receptor α Signaling Pathway Controls Alternative Splicing in the Absence of Ligands in Breast Cancer Cells

“…In particular, SAMD4A , which is a conserved RBP across mammals that controls gene translation and stability, has been recently reported as a BC suppressor. Specifically, it destabilizes the expression of proangiogenic transcripts by physically interacting with the stem loop structure in their 3′UTR through its sterile alpha motif (SAM) domain [ 57 ]. Moreover, we show here that SAMD4A is negatively correlated (r = −0.44, p < 0.0001) with ERα mRNA levels in ERα+ BCs, and accordingly, it was reported to be repressed in BC tissues and cancer cell lines where its low expression is associated with the poor survival of patients and its overexpression inhibited tumor angiogenesis and cancer progression [ 57 ].…”

“…Specifically, it destabilizes the expression of proangiogenic transcripts by physically interacting with the stem loop structure in their 3′UTR through its sterile alpha motif (SAM) domain [ 57 ]. Moreover, we show here that SAMD4A is negatively correlated (r = −0.44, p < 0.0001) with ERα mRNA levels in ERα+ BCs, and accordingly, it was reported to be repressed in BC tissues and cancer cell lines where its low expression is associated with the poor survival of patients and its overexpression inhibited tumor angiogenesis and cancer progression [ 57 ]. Another EMT regulator RBP, QKI , is repressed by apoERα and negatively correlated (r = −0.37; p < 0.0001) with ERα mRNA levels in Erα+ BCs, as previously reported [ 58 ].…”

An in silico pipeline approach uncovers a potentially intricate network involving spike SARS-CoV-2 RNA, RNA vaccines, host RNA-binding proteins (RBPs), and host miRNAs at the cellular level

“…Finally, SAMD4A is a conserved RBP found in a variety of species, and it regulates gene translation and stability. SAMD4A has been linked to angiogenesis and tumor progression in breast cancer, and its low expression in human breast tumor tissues/cells has been linked to a poor prognosis and survival [ 46 ].…”

Identification of Circular RNA-Based Immunomodulatory Networks in Colorectal Cancer

“…The NADH oxidase ENOX1 targets tumour vasculature and can be used in tumour treatment (58,59). Coincidentally, Zhou et al (60) also reported SAMD4A as a novel breast tumour angiogenesis suppressor in breast cancer. ZC3H10 regulates lipid metabolism and may also offer novel routes toward treatments for obesity (61).…”