Dissecting the novel molecular interactions of solute carrier family 4 member 4 (SLC4A4) for prostate cancer (PCa) progression

Abstract

Prostate cancer (PCa) is the most common malignancy diagnosed in men. The purpose of this study was to report the molecular pathways of Homo sapiens solute carrier family 4 member 4 (SLC4A4) in the progression of PCa. Here, we report our findings from clinical specimens of prostatic acinar adenocarcinoma collected from patients. We found that low-grade prostate cancers have higher SLC4A4 expression. We investigated the role of SLC4A4 and the signaling mechanism underlying its role in modulating the PCa progression. Firstly, we reported the SLC4A4/GSK-3β/β-catenin signaling axis, which regulates the clonogenic potential, invasiveness, and metastasis. In this, we found reduced phosphorylation of GSK at serine 21 of α and serine 9 of the β subunit in shSLC4A4 cells of PCa, which ultimately relieved the activity of GSK-3β. This activated GSK-3β phosphorylates β-catenin at Ser33/37 with a subsequently reduced β-catenin level in PCa cells. Our functional analysis revealed that SLC4A4 knockdown retards tumor growth and lowers invasion and migration potential. Secondly, we investigated the SLC4A4/RB axis, which acts to drive cell proliferation. SLC4A4 knockdown decreases the interaction between these molecules with hypophosphorylation of RB protein and cell cycle arrest. Likewise, transcriptome sequencing using the SLC4A4 knockdown in DU145 cells regulates differentiated expressed genes and multiple metabolic pathways. Our results suggest that SLC4A4 may serve as a potential therapeutic target for prostate cancer patients in the future.