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 beta (OST beta), an important subunit of a bile acid export transporter OST alpha-OST beta, was noticeably downregulated in CRC. The decline of OST beta expression in CRC was determined by Western blot and real-time polymerase chain reaction (RTPCR), whereas chromatin immunoprecipitation (ChIP) was used to evaluate the histone acetylation state at the OST beta 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 beta expression increased noticeably because of upregulated H3K27Ac state at OST beta 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 beta expression through modulating H3K27Ac state at OST beta promoter region. Therefore, downregulated expression of p300 in CRC may cause low expression of OST beta in CRC via epigenetic regulation. Generally, we revealed a novel epigenetic mechanism underlying OST beta repression in CRC, hoping this mechanism would help us to understand and inhibit carcinogenesis of CRC. SIGNIFICANCE STATEMENT Organic solute transporter beta (OST beta) 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 beta expression through modulating H3K27Ac state at OST beta promoter region and hence causes low expression of OST beta in colorectal cancer.