Nonylphenol regulates TL1A through the AhR/HDAC2/HNF4α pathway in endothelial cells to promote the angiogenesis of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most malignant cancers worldwide. Nonylphenol (NP) is an endocrine-disruptor chemical and plays an important role in the development of cancers. However, the effects of NP on CRC remain unclear. In this study, we aimed to investigate the potential mechanisms of NP in the pathogenesis of CRC. METHODS: The levels of AhR, TL1A and HDAC2 in CRC tissues and endothelial cells were assessed by RT-qPCR or western blot. CHIP and dual luciferase reporter assays were used to confirm the interaction between AhR and HDAC2, or HNF4α and TL1A. The CCK8, would healing and tube formation assays were conducted to evaluate the proliferation, migration and angiogenesis of HUVECs. Western blot determined HNF4α protein and HNF4α acetylation levels. The secreted TL1A protein was detected by ELISA. The angiogenesis-related factor CD31 was tested by IHC. RESULTS: The expression level of AhR was significantly up-regulated in CRC tissues and endothelial cells. Moreover, NP activated the AhR pathway mediated colorectal endothelial cell angiogenesis and proliferation, while TL1A overexpression resisted these effects caused by NP. Besides, NP was found to modulate HNF4α deacetylation through AhR/HDAC2 to inhibit TL1A. Furthermore, in vivo experiments proved that NP regulated CRC growth and angiogenesis via AhR/HDAC2/HNF4α/TL1A axis. CONCLUSION: This study revealed that NP promoted CRC growth and angiogenesis through AhR/HDAC2/HNF4α/TL1A pathway and could be a new therapeutic target for CRC treatment.