Epigenetic Mechanisms Underlying Organic Solute Transporter β Repression in Colorectal Cancer
| Autor: | Lushan Yu, Jinxiu Lei, Lu Chen, Sheng Ye, Suhang Guo, Su Zeng, Yan Lou, Ying Zhou, Junqing Liu, Chaonan Ye |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pharmacology Regulation of gene expression Small interfering RNA Gene knockdown Lithocholic acid biology Chemistry medicine.disease_cause 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Histone Cancer research medicine biology.protein Molecular Medicine Epigenetics Carcinogenesis Chromatin immunoprecipitation 030217 neurology & neurosurgery |
| Zdroj: | Molecular Pharmacology. 97:259-266 |
| ISSN: | 1521-0111 0026-895X |
| Popis: | 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 (OSTβ), an important subunit of a bile acid export transporter OSTα-OSTβ, was noticeably downregulated in CRC. The decline of OSTβ 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 OSTβ 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, OSTβ expression increased noticeably because of upregulated H3K27Ac state at 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 OSTβ expression through modulating H3K27Ac state at OSTβ promoter region. Therefore, downregulated expression of p300 in CRC may cause low expression of OSTβ in CRC via epigenetic regulation. Generally, we revealed a novel epigenetic mechanism underlying OSTβ 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 OSTβ expression through modulating H3K27Ac state at OSTβ promoter region and hence causes low expression of OSTβ in colorectal cancer. |
| Databáze: | OpenAIRE |
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