Loss of INI1 inhibits the expression of SIDT1 and promotes tumor progression in skull base chordoma by regulating EZH2-mediated H3K27me3

Abstract

Abstract Integrase interactor 1 (INI1) loss is associated with a poor prognosis of skull base chordoma, while the molecular mechanism remains generally unclear. Hence, we herein explored the regulatory mechanism underlying INI1 action in skull base chordoma. We exploited transcriptomic sequencing of 48 skull base chordomas to analyze the INI1-correlated genes, and we found that EZH2 was negatively correlated with INI1. As EZH2 regulated the expression of the repressive histone mark H3K27me3, we applied chromatin immunoprecipitation (ChIP) sequencing of H3K27me3 to investigate the downstream molecules involved. ChIP sequencing and ChIP-qPCR revealed that H3K27me3 directly bound to the SIDT1 promoter, and qRT-PCR verified that H3K27me3 suppressed the transcription of SIDT1. The expression of SIDT1 in skull base chordoma was assessed using immunohistochemical staining and its low expression was associated with a poor prognosis in chordoma patients. When the potential tumor-suppressive effects ofSIDT1 were further investigatedby cytologic experiments, our results verified that SIDT1 played a tumor-suppressive role in chordoma both in vitro and in vivo. In conclusion, these findings suggested the INI1-EZH2-H3K27me3-SIDT1 axis as a possible novel therapeutic target in skull base chordoma.