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.
Highlights
Prostate cancer is one major human malignancy with high incidence, metastasis, and mortality rates due to asymptomatic feature at early stages, which is still listed as the second most common cancer in males and the fifth cause of cancer-related deaths all over the world[1,2]
We focused on three Long non-coding RNAs (lncRNAs) including SChLAP1, CTBP1-AS, and PCGEM1 (Fig. 1A) through further big data analysis of clinical samples
In order to confirm the effects of SChLAP1 on the expression of miR-340-5p, quantitative PCR (qPCR) was performed in DU145 and LNcap cells with SChLAP1 overexpression or knockdown, as well as several other miRNAs all located on the chromosome 5, such as the miR-145-5p and miR-143-3p
Summary
Prostate cancer is one major human malignancy with high incidence, metastasis, and mortality rates due to asymptomatic feature at early stages, which is still listed as the second most common cancer in males and the fifth cause of cancer-related deaths all over the world[1,2]. MicroRNAs (miRNAs), as one large group of noncoding RNAs commonly composed of about 22 nucleotides, have been characterized as major regulators of prostate cancer development and metastasis due to their great capacities of post-transcriptionally modulating gene expression[7,8,9]. We previously discovered that miR-340 was capable of inhibiting the proliferation and metastasis of prostate cancer cells through directly targeting the mouse double minute 2 and p53 signaling pathways[10]. The expression of above-mentioned tumor-suppressing miRNAs, which were encoded by genes localized on the No 5 human chromosome, were all significantly inhibited in prostate cancer cells[10,11,13]. The molecular mechanisms underlying suppressed expression of these miRNAs would broaden our understanding of prostate cancer development
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