Epigenetic Mechanisms Underlying Organic Solute Transporter β Repression in Colorectal Cancer

Colorectal cancer (CRC) is known to be the third most common cancer disease and the fourth-leading cause of cancer-related deaths worldwide. Bile acid, especially deoxycholic acid and lithocholic acid, were revealed to play an important role during carcinogenesis of CRC. In this study, we found organic solute transporter β (OST β ), an important subunit of a bile acid export transporter OST α -OST β , was noticeably downregulated in CRC. The decline of OST β expression in CRC was determined by Western blot and real-time polymerase chain reaction (RT-PCR), whereas chromatin immunoprecipitation (ChIP) was used to evaluate the histone acetylation state at the OST β promoter region in vivo and in vitro. CRC cell lines HT29 and HCT15 were treated with trichostation A (TSA) for the subsequent determination, including RT-PCR, small interfering RNA (siRNA) knockdown, ChIP, and dual-luciferase reporter gene assay, to find out which histone acetyltransferases and deacetylases exactly participated in regulation. We demonstrated that after TSA treatment, OST β expression increased noticeably because of upregulated H3K27Ac state a OSTβ promoter region. We found that stimulating the expression of p300 with CTB (Cholera Toxin B subunit, an activator of p300) and inhibiting p300 expression with C646 (an inhibitor of p300) or siRNA designed for p300 could control OST β expression through modulating H3K27Ac state a OSTβ promoter region. Therefore, downregulated expression of p300 in CRC may cause low expression of OST β in CRC via epigenetic regulation. Generally, we revealed a novel epigenetic mechanism underlying OST β repression in CRC, hoping this mechanism would help us to understand and inhibit carcinogenesis of CRC. SIGNIFICANCE STATEMENT: Organic solute transporter β ( OSTβ ) expression is lower in colon cancer tissues compared with adjacent normal tissues. We revealed the epigenetic mechanisms of it and proved that p300 controls OST β expression through modulating H3K27Ac state a OSTβ promoter region and hence causes low expression of OST β in colorectal cancer.