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Retinoic acid receptor γ (RARγ), a unique member of the nuclear receptor superfamily, plays an important role in the progression of several cancers such as hepatocellular carcinoma, esophageal cancer, and cholangiocarcinoma.However, little is known about regulatory mechanisms of the RARγ activity in colorectal cancer (CRC) progression.In this study, we found that RARγ was frequently overexpressed in human CRC specimens and CRC cell lines, and it mainly resided in the cytoplasm in CRC specimens.RARγ knockdown does not affect CRC cell proliferation.Whats more, flow cytometry analysis suggested that RARγ knockdown does not block the cell cycle.Interestingly, RARγ krnockdown in CRC cells increased their sensitivity to chemotherapeutics via downregulation of multi-drug resistance 1(MDR1), rather than MRP1,MRP2 or MRP3.Further studies suggested that RARγ-positive CRC samples showed higher levels of MDR1 expression and a significantly positive association between RARγ and MDR1 was demonstrated in CRC tissues.Collectively, these results suggest that RARγ may function as an oncogenic driver of chemotherapeutic drugs resistance via its regulation of MDR1, indicating that RARγ might serve as a potential therapeutic target for overcoming chemoresistance of CRC patients.