SChLAP1 promotes prostate cancer development through interacting with EZH2 to mediate promoter methylation modification of multiple miRNAs of chromosome 5 with a DNMT3a-feedback loop

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Cell Death Dis. 2021 Feb 15;12(2):188. doi: 10.1038/s41419-021-03455-8.

ABSTRACT

This study aimed to investigate the mechanism of SChLAP1 (second chromosome locus associated with prostate-1) on microRNA expression in prostate cancer. Differential expression of lncRNAs and microRNA prostate cancer cells were predicted by informatics and confirmed by qRT-PCR. SChLAP1-interacting proteins were characterized by RNA pull-down combined with western blotting, which was verified using RIP and qPCR analysis. Then ChIP assay and DNA pull-down were used to validate the binding of DNMT3a and HEK27me3 with miRNA gene promoters. Target genes of miRNAs were bioinformatically predicted and validated by dual-luciferase reporter assays. The tumorigenicity of prostate cancer cells was assessed using the cancer cell line-based xenograft (CDX) model. We found that SChLAP1 expression was significantly elevated in prostate cancer tissues and cell lines, which was negatively correlated with miR-340 expression. SChLAP1 directly binds with EZH2 and repressed multiple miRNA expression on chromosome 5 including the miR-340-3p in prostate cancer cells through recruiting H3K27me3 to mediate promoter methylation modification of miR-340-5p/miR-143-3p/miR-145-5p to suppress gene transcription. Moreover, DNMT3a was one of the common target genes of miR-340-5p/miR-143-3p/miR-145-5p in prostate cancer cells. And SChLAP1/EZH2 could also promote prostate cancer tumor development via the interaction of microRNA-DNMT3a signaling pathways in xenograft nude mice. Altogether, our results suggest that SChLAP1 enhanced the proliferation, migration, and tumorigenicity of prostate cancer cells through interacting with EZH2 to recruit H2K27me3 and mediate promoter methylation modification of miR-340-5p/miR-143-3p/miR-145-5p with a DNMT3a-feedback loop.

PMID:33589600 | DOI:10.1038/s41419-021-03455-8