Investigating the Role of Serrate RNA Effector Molecule (SRRT) in Driving Advanced Prostate Cancer: An In Silico and In Vitro Analysis

Abstract

Research across multiple cancers implicates Serrate RNA Effector Molecule (SRRT) as a potential oncogene, with studies in glioblastoma showing that high SRRT expression reduces patient survival and promotes proliferation through mechanisms involving microRNA (miR)-6798-3p and monoacylglycerol lipase (MAGL)-mediated prostaglandin E2 (PGE2) production. In liver cancers like cholangiocarcinoma and hepatocellular carcinoma, SRRT overexpression correlates with worsened prognosis, with its knockdown leading to increased PTEN levels and reduced cell proliferation via miR-21 suppression. SRRT also facilitates proliferation in acute myeloid leukemia by modulating miR-6734-3p and in breast cancer through altered splice variants linked to metastasis, while being upregulated in HPV-positive and -negative head and neck cancers. In prostate cancer, SRRT expression is elevated compared to benign tissues and progressively increases in more severe disease subtypes, correlating with worse overall survival and associations with Erythroblast transcription specific (ETS)-related gene (ERG), tumour protein P53 (TP53), and prostate-specific antigen (PSA) levels. Additional studies found higher SRRT levels in tumour-adjacent stroma of high Gleason score prostate cancers compared to those with lower Gleason scores. In this study, high expression of SRRT in prostate cancer was correlated with adverse clinical outcomes, including significantly reduced disease-free survival and higher Gleason group classifications, indicating its role as a negative prognostic marker. Mechanistic studies validate that SRRT controls expression of ERG, a transcription factor protein that is overexpressed in prostate cancer and responsible for driving its progression. Additionally, inhibition of SRRT triggers suppression of oncogenic signaling pathways such as protein kinase B (AKT) and mitogen-activated protein (MAP) kinase, which are critical for survival and proliferation of cells. In vitro studies validate that suppression of SRRT expression triggers a significant loss of proliferative activity in prostate cancer cells. Also, knockdown of SRRT disables metastatic activity of cancer cells profoundly through inhibition of migration and invasion capabilities. Overall, these observations validate SRRT to be a key modulator of prostate cancer progression and metastasis, and its utility in acting as a therapeutic target for suppression of malignant behavior and improvement in prognosis.