Promoter hypermethylation of tumor suppressor genes (TSGs) is a hallmark of prostate cancer (PCa) development and holds promise as a diagnostic and prognostic biomarker. Through global methylation analysis of benign prostatic hyperplasia and PCa tissue samples, we identified dual oxidase 1 (DUOX1), a member of the NADPH oxidase family, as a methylation-driven TSG involved in PCa progression. Elevated DUOX1 expression is associated with improved disease-free and progression-free survival in PCa patients, emphasising its clinical relevance. Mechanistically, we show that de novo DNA methyltransferases (DNMT) -3A and -3B mediate DUOX1 promoter-hypermethylation, while the androgen receptor (AR) represses DUOX1 transcription by forming a negative chromosomal circuit through an enhancer-bound AR-H3K27ac-BRD4 axis. Genetic perturbations or pharmacological interventions with demethylating agents, anti-androgen therapies, or BET inhibitors relieve this repression, leading to increased DUOX1 expression. Functional restoration of DUOX1 in AR-positive PCa cells exhibited strong anti-proliferative and anti-metastatic effects by enhancing extracellular ROS production and reducing AR expression. Furthermore, DUOX1 re-expression selectively activated the cellular glucuronidation pathway, disrupting androgen signalling. Collectively, our findings establish DUOX1 as a methylation-driven, AR-regulated tumor suppressor and a promising biomarker for early diagnosis and targeted therapy in prostate adenocarcinoma.

Background: Exploring the potential of BOLA3-DT as a diagnostic biomarker in prostate cancer. Methods: Expression of the lncRNA BOLA3-DT was analyzed between normal and tumor samples in the GDC TCGA PRAD (Genomic Data Commons: The Cancer Genome Atlas Prostate Adenocarcinoma Collection) dataset. Disease progression-related clinicopathological parameters such as serum PSA level (ng/ml) and Gleason score were associated with the expression of BOLA3-DT using the same GDC TCGA PRAD dataset. To validate these findings, the expression of BOLA3-DT was checked in our sample set of 15 PCa (prostate cancer) and 15 BPH (benign hypertrophy of the prostate) patients. Results: In the GDC TCGA PRAD dataset, the expression of the lncRNA BOLA3-DT was significantly downregulated in prostate cancer tissue samples ( n = 492) compared to adjacent normal ( n = 52; p < 0.0001), and, there was a significant negative correlation between the expression of the lncRNA BOLA3-DT and the serum PSA level ( p < 0.01). However, no significant association was found between the lncRNA BOLA3-DT expression and the Gleason score ( p > 0.05). In this study, it was found that BOLA3-DT was downregulated in PCa tissue samples compared to BPH samples ( p > 0.05). In the GDC TCGA PRAD dataset, it was revealed that BOLA3-DT could serve as an excellent diagnostic marker with a sensitivity of 86.9% and a specificity of 84.6% (AUC-0.916). Conclusion: LncRNA BOLA3-DT, a novel long non-coding RNA, was found to be downregulated in prostate cancer. The expression of the lncRNA BOLA3-DT can serve as a diagnostic marker in prostate cancer.

The role of epigenetic alteration in prostate cancer pathogenesis was reported. We aimed to analyze dysregulation of DNA methylase (DNA methyl transferase/DNMT) and demethylase (ten eleven translocase/TET) and the associated interplay between them during prostate tumorigenesis. Promoter methylation and RNA/protein expression of selected DNMT and TETs were analysed in normal prostate, benign prostatic hyperplasia (BPH), and prostate cancer (PCa). Genomic 5-hydroxymethylcytosine (5hmC) level was detected and correlated with DNMT and TET proteins. Clinicopathological association of molecular data was done. Our data revealed a very low frequency of promoter methylation for DNMT1 (5-3% and high frequency for TET1 (22-38%), TET2 (68-90 %), and TET3 (43-32 %) in BPH and PCa. The promoter methylation of DNMT1 (p = 0.019) showed a significantly decreasing trend, while that of TET1 (p = 0.0005) and TET2 (p < 0.0001) showed an increasing trend from normal prostate to BPH to PCa, indicating their epigenetic dysregulation during prostate tumorigenesis. RNA/protein overexpression of DNMT1 and reduced expression of TET1 and TET2 in PCa compared to BPH were associated with the promoter methylation status of genes. The 5hmC level was significantly lower in PCa than in BPH and correlated negatively with DNMT1 but positively with TET1 and TET2 proteins, suggesting dysregulation of DNA methylase and de-methylase activities during prostate tumorigenesis. Lastly, tumors having methylated TET1 and TET2 promoters showed advanced clinicopathological features (a higher PSA level/Gleason score) and increased risk of bone metastasis. In conclusion, DNMT1 upregulation and epigenetic silencing of TET1 and TET2 was seen during PCa development. TET1 and TET2 promoter methylation has prognostic importance.

Research works suggested the role of long non-coding RNAs (lncRNAs) in pathogenesis of clear cell renal cell carcinoma (ccRCC). lncRNA HAGLR is studied in several malignancies, but not in ccRCC. From The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) dataset, we analyzed molecular alterations of HAGLR and constructed a competitive endogenous RNA (ceRNA) network with related miRNAs and mRNAs. Gene Ontology analysis was done to identify important pathways enriched with HAGLR recovered mRNAs. Clinical importance of HAGLR and related mRNAs was assessed and, the impact of selected mRNA-encoding genes on tumor immune infiltration was studied using TIMER. HAGLR expression was reduced in ccRCC than in normal kidneys, and correlated significantly with gene promoter methylation. Low HAGLR level in tumors showed diagnostic potency, and was associated with clinicopathological parameters (stage/grade/metastasis) and poor patient survival. The HAGLR-associated ceRNA network constituted 13 miRNAs and 23 mRNAs differentially expressed in the TCGA-KIRC dataset. From HAGLR recovered mRNA-encoding genes, we developed a 5-gene (PAQR5, ARHGAP24, HABP4, PDLIM5, and RPS6KA2) prognostic signature in the training dataset and validated it in testing as well as entire datasets. The expression level of signature genes showed negative correlation with tumor infiltration of immune cells having adverse impact on ccRCC prognosis and also with tumor derived chemokines facilitating the infiltration. In conclusion, HAGLR seemed to play a tumor suppressive role in ccRCC. HAGLR and associated gene signature may have implementation in improving existing prognostic measure and developing effective immunotherapeutic strategies for ccRCC.

Long non-coding RNAs (lncRNAs) have been gaining importance in the field of cancer research in recent years. PRNCR1 ( prostate cancer-associated non-coding RNA1 ) is a 12.7 kb, intron-less lncRNA found to play an oncogenic role in malignancy of diverse organs including prostate, breast, lung, oral cavity, colon and rectum. Single-nucleotide polymorphisms (SNPs) of PRNCR1 locus have been found to be associated with cancer susceptibility in different populations. In this review, an attempt has been made for the first time to summarize all sorts of available data on PRNCR1 to date from relevant databases (GeneCard, LncExpDB, Ensembl genome browser, and PubMed). As functional roles of PRNCR1 , miRNA (microRNA) sponging was mostly highlighted in the pathogenesis of different cancer; in addition, an association of the lncRNA with chromatin-modifying complex to enhance androgen receptor-mediated gene transcription was reported in prostate cancer. Diagnostic and prognostic importance of PRNCR1 was found in some malignancies suggesting potency of the lncRNA to serve as a clinical biomarker. For PRNCR1 SNPs, although cancer susceptibility of the risk alleles/genotypes was reported in different populations, majorities of the findings were not replicated and underlying molecular mechanisms remained unexplored. Therapeutic implication of PRNCR1 was not studied well and future research may come up in this direction for intervening novel strategies to fight against cancer.

In understanding the role of non-coding RNA in the pathogenesis of oxidative stress-induced urologic cancer, the present study focused on available data of miR-21, an oncogenic miRNA from published literature, in the malignancy of human prostate. miR-21 is over-expressed under oxidative stress, and it serves as a mediator to upregulate ROS (reactive oxygen species) induced signaling pathways including AR (androgen receptor), PI3K/Akt, RTK/ERK, and so on during carcinogenesis of prostate. In prostate cancer, association of miR-21 with aggressive tumor phenotypes, poor patient survival, and differential response of patients to conventional treatment measures indicated its (miR-21) potency to predict disease outcome as a prognostic biomarker. In the body fluid of patients, availability of miR-21 and its prognostic value may be explored to evaluate disease outcomes in non-invasive methods. miR-21 has been targeted therapeutically by synthetic and naturally occurring substances with significant suppression of tumorigenicity of cancer cells. However extensive in vivo research is warranted with therapeutic measures to determine the effective dose and to develop suitable delivery system for initiating their bedside implementation.