CLDN8, an androgen-regulated gene, promotes prostate cancer cell proliferation and migration

Abstract

The proliferation of prostate cancer cells is controlled by androgen receptor (AR) signaling pathway. However, the function of AR target genes has not been fully elucidated. In the previous studies, we have identified global AR binding sites (ARBSs) and AR target genes in prostate cancer cells. Here, we focused on Claudin 8 (CLDN8), a protein constituting tight junction in cell membrane. We found one ARBS in the promoter region and two functional androgen-responsive elements (AREs) in the sequence. Reporter assay demonstrated transcriptional activation of the CLDN8 promoter by androgen is dependent on these AREs. Furthermore, CLDN8 mRNA is induced by androgen time dependently and the induction is blocked by AR inhibitor, suggesting that AR is involved in the transcriptional activation. In addition, our functional analyses by overexpression and knockdown of CLDN8 mRNA indicate that CLDN8 promotes prostate cancer cell proliferation and migration. CLDN8 was overexpressed in prostate cancer clinical samples compared to benign tissues. Furthermore, we found that CLDN8 regulates intracellular signal transduction and stabilizes cytoskeleton. Taken together, these results indicate that CLDN8 functions as an AR downstream signal to facilitate the progression of prostate cancer. CLDN8 may be a novel molecular target for prostate cancer therapy.

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