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Effect of depletion of PRCAT71 and KHSRP on gene expression in prostate cancer cells

ABSTRACT: Mounting evidence indicates that long non-coding RNAs (lncRNAs) play vital roles in tumorigenesis and progression of cancers. However, the functions and regulatory mechanisms of lncRNAs in prostate cancer (PCa) are still largely unknown. In this study, we discovered a PCa-specific lncRNA, PRCAT71, significantly highly expressed in metastatic and primary PCa compared to benign prostate tissues. Silencing PRCAT71 inhibited cancerous properties of PCa cells, as well as androgen receptor (AR) signaling. Mechanismly, PRCAT71 acts as a scaffold to recruit KH-type splicing regulatory protein (KHSRP) to AR mRNA and stabilize AR mRNA. Furthermore, PRCAT71 is transcriptionally regulated by AR, thus forming a positive regulatory loop between AR and PRCAT71 in PCa. Our findings demonstrate that the PRCAT71-KHSRP-AR axis is a promising therapeutic target to treat PCa.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240059 | GEO | 2024/10/16

REPOSITORIES: GEO

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Project description:Breast cancer has become the most common type of cancers worldwide. Its high prevalence and malignant features are associated with various environmental factors and molecules. The KH-type splicing regulatory protein (KHSRP) participates in the development of breast cancer, while the underlying mechanisms are largely unknown. In this study, we silenced KHSRP expression in MDA-MB-231 cells by small interfering RNA (siKHSRP), and then assessed its effects on cellular features. Finally, we performed whole transcriptome sequencing (RNA-seq) experiments to explore the downstream targets of KHSRP, and validated their changed pattern using quantitative polymerase chain reaction. We found KHSRP showed higher expression level and was associated with worse prognosis in breast cancer patients. In siKHSRP samples, the proliferation, invasion, and migration abilities were significantly repressed compared with negative control (NC) samples, while the apoptosis level was increased. By investigating the RNA-seq data, we found KHSRP globally regulates the expression and alternative splicing profiles of MDA-MB-231 cells by identifying 1632 differentially expressed genes (DEGs) and 1630 HKSRP-regulated AS events (RASEs). Functional enriched analysis of DEGs demonstrated that cilium assembly and movement and extracellular matrix organization pathways were specifically enriched in up DEGs, consistent with the repressed migration and invasion abilities in siKHSRP cells. Interestingly, the cell cycle and DNA damage and repair associated pathways were enriched in both down DEGs and RASE genes, suggesting that KHSRP may modulate cell proliferation by regulating genes in these pathways. Finally, we validated the changed expression and AS patterns of genes in cell cycle and DNA damage/repair pathways. Expression levels of BIRC5, CCNA2, CDK1, FEN1, FOXM1, PTTG1, and UHRF1 were downregulated in siKHSRP samples. The AS patterns of PARK7, UBE2A, UBE2D3, NPM1, ERCC1, CSNK1E, CENPX, and SWI5 were also dysregulated in siKHSRP samples. In summary, our study comprehensively explored the downstream targets and their functions of KHSRP in breast cancer cells, highlighting the molecular mechanisms of KHSRP on the oncogenic features of breast cancer. The identified molecular targets could be served as potential therapeutic targets for breast cancer in future.

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Effect of depletion of PRCAT71 and KHSRP on gene expression in prostate cancer cells

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