Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence

Hepatocyte nuclear factor 4 alpha (HNF4 alpha, NR2A1) is a highly conserved member of the nuclear receptor superfamily. Recent advances reveal that it is a key transcriptional regulator of genes, broadly involved in xenobiotic and drug metabolism and also cancers of gastrointestinal tract. However, the exact functional roles of HNF4 alpha in prostate cancer progression are still not fully understood. In this study, we determined the functional significance of HNF4 alpha in prostate cancer. Our results showed that HNF4 alpha exhibited a reduced expression pattern in clinical prostate cancer tissues, prostate cancer cell lines and xenograft model of castration-relapse prostate cancer. Stable HNF4 alpha knockdown not only could promote cell proliferation and suppress doxorubicin (Dox)-induced cellular senescence in prostate cancer cells, but also confer resistance to paclitaxel treatment and enhance colony formation capacity and in vivo tumorigenicity of prostate cancer cells. On the contrary, ectopic overexpression of HNF4 alpha could significantly inhibit the cell proliferation of prostate cancer cells, induce cell-cycle arrest at G(2)/M phase and trigger the cellular senescence in prostate cancer cells by activation of p21 signal pathway in a p53-independent manner via its direct transactivation of CDKN1A. Together, our results show that HNF4 alpha performs a tumor suppressor function in prostate cancer via a mechanism of p21-driven cellular senescence.