Oncogenic retinoic acid receptor [alpha] promotes human colorectal cancer growth through simultaneously regulating p21 transcription and GSK3[beta]/[beta]-catenin signaling

Retinoic acid receptor α (RARα) plays important roles in the progression of several cancers such as leukemia, breast cancer, and lung cancer. In this study, we demonstrated that RARα protein was frequently overexpressed in human CRC specimens and CRC cell lines. RARα knockdown decreased cell survival, proliferation, and colony formation in vitro and tumorigenic potential in nude mice. Specifically, RARα knockdown inhibited cell cycle progression at G1 phase through upregulation of cell cycle inhibitor p21, and downregulation of cyclinD1. Furthermore, RARα was directly recruited to the p21 promoter to inhibit the expression of p21. Simultaneously, RARα contributed to the progression of CRC cells in part due to upregulation of cyclinD1 via activation of GSK3β/β-catenin pathway. Molecular mechanism studies revealed RARα interacted with GSK3β and led to decreased expression of GSK3β at ser9, followed by increased β-catenin expression. Taken together, our results signified the importance of RARα in CRC and demonstrated that RARα promotes CRC progression through suppressing p21 transcription and enhancing GSK3β/β-catenin signaling. RARα might become a potential molecular target for the treatment of CRC.