RNA 测序分析表明 N-钙黏蛋白通过关键基因的表观遗传修饰促进前列腺癌的进展。

RNA-Sequencing Analysis Indicates That N-Cadherin Promotes Prostate Cancer Progression by the Epigenetic Modification of Key Genes.

机构信息

Department of Urology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.

Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.

出版信息

DNA Cell Biol. 2023 Sep;42(9):563-577. doi: 10.1089/dna.2023.0089. Epub 2023 Aug 4.

DOI:10.1089/dna.2023.0089

PMID:37540080

Abstract

N-cadherin (cadherin-2 [CDH2]) is widely known as the promoter of prostate cancer (PCa) invasion and castration resistance. However, the biological mechanism of N-cadherin in PCa progression is unclear. In this study, we overexpressed N-cadherin in LNCaP cells and downregulated N-cadherin in PC3 cells by lentiviral transduction. Then, differentially expressed genes (DEGs) and dysregulated biological functions were investigated through RNA sequencing (RNA-seq) analyses. We found 13 long noncoding RNA (lncRNA) transcripts, 72 messenger RNA (mRNA) transcripts, and 3 integrated genes were dysregulated by N-cadherin. In the disease enrichment, bone cancer, and neurodegenerative and nervous system diseases were associated with N-cadherin in the circular RNA (circRNA; PC3 versus [vs.,/] LNCaP [PC3/LNCaP] comparison) and DEG analysis (LNCaP_oe_CDH2 vs. LNCaP_oe_NC [LNCaP_oe_CDH2/NC] comparison). Epigenetic reprogramming, such as nucleic acid binding, and chromatin and histone modifications, was enriched in Gene Ontology (GO) analysis (DEGs in LNCaP_oe_CDH2/NC and PC3_sh_NC/CDH2, and host genes of circRNA in PC3/LNCaP). Transcriptional misregulation in cancer, post-translational protein modification, gene expression, and generic transcription pathways were dysregulated in the pathway enrichment analysis (host genes of circRNA in PC3/LNCaP, and DEGs in LNCaP_oe_CDH2/NC and PC3_sh_NC/CDH2). Verifying DEGs through TCGA-PRAD dataset revealed six oncogenes (ARHGEF1, GRAMD1A, GTF2H4, MAPK8IP3, POLD1, and PTBP1) that were commonly upregulated by N-cadherin and in advanced PCa stages. In summary, we identified several oncogenes and biological functions associated with N-cadherin expression in PCa cells. N-cadherin may trigger epigenetic reprogramming in PCa cells to promote tumor progression.

摘要

N-钙黏蛋白（钙黏蛋白-2 [CDH2]）被广泛认为是促进前列腺癌（PCa）侵袭和去势抵抗的因素。然而，N-钙黏蛋白在 PCa 进展中的生物学机制尚不清楚。在本研究中，我们通过慢病毒转导过表达 LNCaP 细胞中的 N-钙黏蛋白，下调 PC3 细胞中的 N-钙黏蛋白。然后，通过 RNA 测序（RNA-seq）分析研究差异表达基因（DEG）和失调的生物学功能。我们发现 13 个长链非编码 RNA（lncRNA）转录本、72 个信使 RNA（mRNA）转录本和 3 个整合基因受 N-钙黏蛋白调控。在疾病富集分析中，骨癌、神经退行性疾病和神经系统疾病与环状 RNA（circRNA；PC3 与 LNCaP 的比较[PC3/LNCaP]）和 DEG 分析（LNCaP_oe_CDH2 与 LNCaP_oe_NC 的比较[LNCaP_oe_CDH2/NC]）中的 N-钙黏蛋白相关。基因本体论（GO）分析（LNCaP_oe_CDH2/NC 和 PC3_sh_NC/CDH2 中的 DEG 和 circRNA 的宿主基因）中富集了表观遗传重编程，如核酸结合、染色质和组蛋白修饰。通路富集分析（circRNA 的宿主基因在 PC3/LNCaP 中，DEG 在 LNCaP_oe_CDH2/NC 和 PC3_sh_NC/CDH2 中）中失调了转录失调、癌症的翻译后蛋白质修饰、基因表达和通用转录途径。通过 TCGA-PRAD 数据集验证 DEG 显示，六个癌基因（ARHGEF1、GRAMD1A、GTF2H4、MAPK8IP3、POLD1 和 PTBP1）被 N-钙黏蛋白共同上调，并在 PCa 的晚期阶段上调。总之，我们鉴定了与 PCa 细胞中 N-钙黏蛋白表达相关的几个癌基因和生物学功能。N-钙黏蛋白可能触发 PCa 细胞中的表观遗传重编程，以促进肿瘤进展。