The RNA-binding protein HuR confers oxaliplatin resistance of colorectal cancer by upregulating CDC6

Human antigen R (HuR) is a RNA-binding protein that post-transcriptionally regulates many cancer-trait genes. CDC6, a central regulator of DNA replication, is regulated by HuR. In this study, we investigated the role of HuR in CRC tumorigenesis and oxaliplatin (L-OHP) resistance, as well as the underlying mechanisms involving CDC6. We detected increased HuR and CDC6 expression, along with a positive correlation between the two in human CRC tissues. HuR overexpression increased CRC cell proliferation in vitro and xenograft tumor growth in vivo, and induced resistance to L-OHP. In contrast, HuR knockdown sensitized CRC cells to L-OHP. CDC6 overexpression increased while CDC6 knockdown decreased CRC cell malignant behaviors (growth, DNA synthesis, EMT, migration and invasion) and L-OHP resistance in vitro. Moreover, L-OHP resistance induced by HuR overexpression was reversed by CDC6 knockdown. Mechanistically, the results from our luciferase reporter and ribonucleoprotein immunoprecipitation assays indicated that HuR upregulates CDC6 by binding to CDC6 39-UTR. Taken together, our findings identified HuR9s regulation of CDC6 as an essential mechanism driving CRC tumorigenesis and L-OHP resistance, and this mechanism may represent a potential target for overcoming drug resistance in CRC.