piRNA PROPER Suppresses DUSP1 Translation by Targeting N6-Methyladenosine-Mediated RNA Circularization to Promote Oncogenesis of Prostate Cancer.

Genetic and epigenetic alterations occur in many physiological and pathological processes. The existing knowledge regarding the association of PIWI-interacting RNAs (piRNAs) and their genetic variants on risk and progression of prostate cancer (PCa) is limited. In this study, three genome-wide association study datasets are combined, including 85,707 PCa cases and 166,247 controls, to uncover genetic variants in piRNAs. Functional investigations involved manipulating piRNA expression in cellular and mouse models to study its oncogenetic role in PCa. A specific genetic variant, rs17201241 is identified, associated with increased expression of PROPER (piRNA overexpressed in prostate cancer) in tumors and are located within the gene, conferring an increased risk and malignant progression of PCa. Mechanistically, PROPER coupled with YTHDF2 to recognize N6-methyladenosine (m6A) and facilitated RNA-binding protein interactions between EIF2S3 at 5'-untranslated region (UTR) and YTHDF2/YBX3 at 3'-UTR to promote DUSP1 circularization. This m6A-dependent mRNA-looping pattern enhanced DUSP1 degradation and inhibited DUSP1 translation, ultimately reducing DUSP1 expression and promoting PCa metastasis via the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Inhibition of PROPER expression using antagoPROPER effectively suppressed xenograft growth, suggesting its potential as a therapeutic target. Thus, targeting piRNA PROPER-mediated genetic and epigenetic fine control is a promising strategy for the concurrent prevention and treatment of PCa.

Genetic variant in a BaP-activated super-enhancer increases prostate cancer risk by promoting AhR-mediated FAM227A expression.

Genetic variants in super-enhancers (SEs) are increasingly implicated as a disease risk-driving mechanism. Previous studies have reported an associations between benzo[a]pyrene (BaP) exposure and some malignant tumor risk. Currently, it is unclear whether BaP is involved in the effect of genetic variants in SEs on prostate cancer risk, nor the associated intrinsic molecular mechanisms. In the current study, by using logistic regression analysis, we found that rs5750581T>C in 22q-SE was significantly associated with prostate cancer risk (odds ratio = 1.26, P = 7.61 × 10 -5). We also have found that the rs6001092T>G, in a high linkage disequilibrium with rs5750581T>C ( r 2 = 0.98), is located in a regulatory aryl hydrocarbon receptor (AhR) motif and may interact with the FAM227A promoter in further bioinformatics analysis. We then performed a series of functional and BaP acute exposure experiments to assess biological function of the genetic variant and the target gene. Biologically, the rs6001092-G allele strengthened the transcription factor binding affinity to AhR, thereby upregulating FAM227A, especially upon exposure to BaP, which induced the malignant phenotypes of prostate cancer. The current study highlights that AhR acts as an environmental sensor of BaP and is involved in the SE-mediated prostate cancer risk, which may provide new insights into the etiology of prostate cancer associated with the inherited SE variants under environmental carcinogen stressors.

Benzo[a]pyrene exposure affects colorectal cancer susceptibility by regulating ERß-mediated LINC02977 transcription.

Environmental pollutants known as polycyclic aromatic hydrocarbons (PAHs) are produced through the incomplete combustion of organic material. While PAHs have been investigated as genotoxicants, they can also operate through nongenotoxic pathways in estrogen-dependent malignancies, such as breast, cervical and ovarian cancer. However, whether PAHs induce colorectal cancer (CRC) risk through estrogenic effects is still illusive. Here, we systematically investigated the abnormal expression and activation of estrogen receptor beta (ERß) regulated by PAHs in CRC as well as the underlying mechanisms of ERß-mediated CRC risk. Based on the 300 plasma samples from CRC patients and healthy controls detected by GC-MS/MS, we found that the plasma concentrations of benzo[a]pyrene (BaP) were significantly higher in CRC cases than in healthy controls, with significant estrogenic effects. Moreover, histone deacetylase 2 (HDAC2)-induced deacetylation of the promoter decreases ERß expression, which is associated with poor overall survival and advanced tumor stage. The study also revealed that BaP and estradiol (E2) had different carcinogenic effects, with BaP promoting cell proliferation and inhibiting apoptosis, while E2 had the opposite effects. Additionally, this study mapped ERß genomic binding regions by performing ChIP-seq and ATAC-seq and identified genetic variants of rs1411680 and its high linkage disequilibrium SNP rs6477937, which were significantly associated with CRC risk through meta-analysis of two independent Chinese population genome-wide association studies comprising 2,248 cases and 3,173 controls and then validation in a large-scale European population. By integrating data from functional genomics, we validated the regulatory effect of rs6477937 as an ERß binding-disrupting SNP that mediated allele-specific expression of LINC02977 in a long-range chromosomal interaction manner, which was found to be highly expressed in CRC tissues. Overall, this study suggests that the different active effects on ERß by PAHs and endogenous E2 may play a crucial role in the development and progression of CRC and highlights the potential of targeting ERß and its downstream targets for CRC prevention and treatment.

Construction, evaluation, and AOP framework-based application of the EpPRS as a genetic surrogate for assessing environmental pollutants.

BACKGROUND: Environmental pollutant measurement is essential for accurate health risk assessment. However, the detection of humans' internal exposure to pollutants is cost-intensive and consumes time and energy. Polygenic risk scores (PRSs) have been widely applied in genetic studies of complex trait diseases. It is important to construct a genetically relevant environmental surrogate for pollutant exposure and to explore its utility for disease prediction and risk assessment. OBJECTIVES: This study enrolled 714 individuals with complete genomic data and exposomic data on 22 plasma-persistent organic pollutants (POPs). METHODS: We first conducted 22 POP genome-wide association studies (GWAS) and constructed the corresponding environmental pollutant-based PRS (EpPRS) by clumping and P value thresholding (C + T), lassosum, and PRS-CS methods. The best-fit EpPRS was chosen by its regression R2. An adverse outcome pathway (AOP) framework was developed to assess the effects of contaminants on candidate diseases. Furthermore, Mendelian randomization (MR) analysis was performed to explore the causal association between POPs and cancer risk. RESULTS: The C + T method produced the best-performing EpPRSs for 7 PCBs and 4 PBDEs. EpPRSs replicated the correlations of environmental exposure measurements based on consistent patterns. The diagnostic performance of type 2 diabetes mellitus (T2DM) PRS was improved by the combined model of T2DM-EpPRS of PCB126/BDE153. Finally, the AKT1-mediated AOP framework illustrated that PCB126 and BDE153 may increase the risk of T2DM by decreasing AKT1 phosphorylation through the cGMP-PKG pathway and promoting abnormal glucose homeostasis. MR analysis showed that digestive system tumors, such as colorectal cancer and biliary tract cancer, are more sensitive to POP exposure. CONCLUSIONS: EpPRSs can serve as a proxy for assessing pollutant internal exposure. The application of the EpPRS to disease risk assessment can reveal the toxic pathway and mode of action linking exposure and disease in detail, providing a basis for the development of environmental pollutant control strategies.