RXR agonist, Bexarotene, effectively reduces drug resistance via regulation of RFX1 in embryonic carcinoma cells.

Aberrant expression of multidrug resistance (MDR) proteins is one of the features of cancer stem cells (CSCs) that make them escape chemotherapy. A well-orchestrated regulation of multiple MDRs by different transcription factors in cancer cells confers this drug resistance. An in silico analysis of the major MDR genes revealed a possible regulation by RFX1 and Nrf2. Previous reports also noted that Nrf2 is a positive regulator of MDR genes in NT2 cells. But we, for the first time, report that Regulatory factor X1 (RFX1), a pleiotropic transcription factor, negatively regulates the major MDR genes, Abcg2, Abcb1, Abcc1, and Abcc2, in NT2 cells. The levels of RFX1 in undifferentiated NT2 cells were found to be very low, which significantly increased upon RA-induced differentiation. Ectopic expression of RFX1 reduced the levels of transcripts corresponding to MDRs and stemness-associated genes. Interestingly, Bexarotene, an RXR agonist that acts as an inhibitor of Nrf2-ARE signaling, could increase the transcription of RFX1. Further analysis revealed that the RFX1 promoter has binding sites for RXRα, and upon Bexarotene exposure RXRα could bind and activate the RFX1 promoter. Bexarotene, alone or in combination with Cisplatin, could inhibit many cancer/CSC-associated properties in NT2 cells. Also, it significantly reduced the expression of drug resistance proteins and made the cells sensitive towards Cisplatin. Our study proves that RFX1 could be a potent molecule to target MDRs, and Bexarotene can induce RXRα-mediated RFX1 expression, therefore, would be a better chemo-assisting drug during therapy.

RFX1: a promising therapeutic arsenal against cancer.

Regulatory factor X1 (RFX1) is an evolutionary conserved transcriptional factor that influences a wide range of cellular processes such as cell cycle, cell proliferation, differentiation, and apoptosis, by regulating a number of target genes that are involved in such processes. On a closer look, these target genes also play a key role in tumorigenesis and associated events. Such observations paved the way for further studies evaluating the role of RFX1 in cancer. These studies were indispensable due to the failure of conventional chemotherapeutic drugs to target key cellular hallmarks such as cancer stemness, cellular plasticity, enhanced drug efflux, de-regulated DNA repair machinery, and altered pathways evading apoptosis. In this review, we compile significant evidence for the tumor-suppressive activities of RFX1 while also analyzing its oncogenic potential in some cancers. RFX1 induction decreased cellular proliferation, modulated the immune system, induced apoptosis, reduced chemoresistance, and sensitized cancer stem cells for chemotherapy. Thus, our review discusses the pleiotropic function of RFX1 in multitudinous gene regulations, decisive protein-protein interactions, and also its role in regulating key cell signaling events in cancer. Elucidation of these regulatory mechanisms can be further utilized for RFX1 targeted therapy.