5-Methylcytosine RNA Methyltransferases-Related Long Non-coding RNA to Develop and Validate Biochemical Recurrence Signature in Prostate Cancer.

Ke Wang,Houhua Lai,Chuanfan Zhong,Weibo Zhong,Pengxiang Zheng,Zining Long,Xiangming Mao,Jianming Lu,Shuo Wang,Taowei Yang,Yufei Guo

doi:10.3389/fmolb.2021.775304

Abstract

The effects of 5-methylcytosine in RNA (m5C) in various human cancers have been increasingly studied recently; however, the m5C regulator signature in prostate cancer (PCa) has not been well established yet. In this study, we identified and characterized a series of m5C-related long non-coding RNAs (lncRNAs) in PCa. Univariate Cox regression analysis and least absolute shrinkage and selector operation (LASSO) regression analysis were implemented to construct a m5C-related lncRNA prognostic signature. Consequently, a prognostic m5C-lnc model was established, including 17 lncRNAs: MAFG-AS1, AC012510.1, AC012065.3, AL117332.1, AC132192.2, AP001160.2, AC129510.1, AC084018.2, UBXN10-AS1, AC138956.2, ZNF32-AS2, AC017100.1, AC004943.2, SP2-AS1, Z93930.2, AP001486.2, and LINC01135. The high m5C-lnc score calculated by the model significantly relates to poor biochemical recurrence (BCR)-free survival (p < 0.0001). Receiver operating characteristic (ROC) curves and a decision curve analysis (DCA) further validated the accuracy of the prognostic model. Subsequently, a predictive nomogram combining the prognostic model with clinical features was created, and it exhibited promising predictive efficacy for BCR risk stratification. Next, the competing endogenous RNA (ceRNA) network and lncRNA–protein interaction network were established to explore the potential functions of these 17 lncRNAs mechanically. In addition, functional enrichment analysis revealed that these lncRNAs are involved in many cellular metabolic pathways. Lastly, M AFG-AS1 was selected for experimental validation; it was upregulated in PCa and probably promoted PCa proliferation and invasion in vitro. These results offer some insights into the m5C's effects on PCa and reveal a predictive model with the potential clinical value to improve the prognosis of patients with PCa.

Highlights

Prostate cancer (PCa) ranks as the second most commonly diagnosed tumor and the fifth leading cause of mortality in men worldwide, with an increasing trend in incidence (Sung et al, 2021)
We searched and identified 13 m5C- regulators from published articles, and The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets of prostate adenocarcinoma were downloaded for further analysis
After extracting the expression matrixes of these m5C regulators and all long non-coding RNA (lncRNA) in the TCGA dataset and excluding lncRNAs with Fragments Per Kilobase Million (FPKM) < 1 (Fragments Per kilobase Million), we performed a Pearson correlation analysis between these m5C-related genes and 2,590 lncRNAs to determine whether a lncRNA was correlated with the m5C modification (|Pearson R| > 0.4 and p < 0.05), and we included 678 qualified lncRNAs into logistic regression analysis and univariate Cox regression analysis for further screening (Supplementary Tables S1 and S2)

Summary

Introduction

Prostate cancer (PCa) ranks as the second most commonly diagnosed tumor and the fifth leading cause of mortality in men worldwide, with an increasing trend in incidence (Sung et al, 2021). High heterogeneity is commonly considered to be one of the significant hallmarks of PCa. The high heterogeneity, mainly characterized by multiple genomic alterations, contributes to cancer initiation, progression and metastasis, and difficulty for the diagnosis, prognosis, and treatment (Dinescu et al, 2019). In addition to genomic aberrations, epigenetic modifications that recently have risen to fame have been reported to be associated with cancer progression and might provide new insights to innovate novel diagnostic and therapeutic strategies. 5methylcytosine in DNA (5mC) and its oxidized derivatives, including 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and as 5-carboxylcytosine (5caC) are the most welldocumented ones at the DNA level (Bohnsack et al, 2019), functioning epigenetically as gene expression regulators via plenty of diverse mechanisms. 5-methylcytosine is detected in several RNA species (m5C), emerging as a critical modulator in many aspects of gene expression, including RNA export, ribosome assembly, translation, and RNA stability (Bohnsack et al, 2019; Dou et al, 2020; Rong et al, 2021)

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Conclusion