Multifaceted functions of transcription regulatory factor X6 (RFX6): from pancreatic development to cancer progression

Regulatory factor X6 (RFX6) is defined as the sixth member of the RFX family based on its highly conserved and specific wing-helix DNA-binding domain. Its expression in adults is predominantly localized to pancreatic islets, small intestine, and colon. Extensive research has demonstrated that RFX6 regulates cellular processes, such as pancreatic development, differentiation of islet progenitor cells, and insulin secretion, through the modulation of specific miRNAs (such as miR145 and miR195) and mRNAs (such as Pdx1, Neurod1, GCK, and Abcc8). Hence, mutations and deletions in RFX6 have been linked to the onset of various types of diabetes, including type 2 diabetes, Maturity-onset diabetes of the young, neonatal diabetes mellitus, especially Mitchell-Riley Syndrome (MRS). Specifically, homozygous mutations in RFX6 impede the proper differentiation of pancreatic progenitor cells, leading to inhibition of pancreatic head-tail development and endocrine cell formation, thereby contributing to the pathogenesis of MRS. Furthermore, examination of RFX6 target genes reveals a potential association with tumor development, indicating that RFX6 may play a role in cancer progression. Dysregulated expression or mutations of the RFX6 gene in prostate cancer, hepatocellular carcinoma, gastric cancer, melanoma, and other tumors have garnered significant interest, with studies showing that such alterations affect tumor cell proliferation, migration, and invasion, and are correlated with an unfavorable clinical prognosis in patients carrying RFX6 mutations. This review delves into the various functions of RFX6, emphasizing its crucial regulatory roles in pancreatic development, tumorigenesis, and progression. In addition, recent advancements in MRS therapy are outlined, underscoring the importance of RFX6-targeted therapy in MRS and cancer.