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Pathway of DNA methylation-age interaction effect on survival of lung adenocarcinomas (LUAD) patients.
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DNA methylation changes during aging, but it remains unclear whether the effect of DNA methylation on lung cancer survival varies with age. Such an effect could decrease prediction accuracy and treatment efficacy. We performed a methylation-age interaction analysis using 1,230 early-stage lung adenocarcinoma patients from five cohorts. A Cox propor...
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... autophagy can act as a mechanism of tumor resistance to chemotherapy agents and lead to antagonistic effects of gefitinib combined with cisplatin in NSCLC treatment, which may contribute to poor therapeutic effectiveness and patient prognosis [22,23]. Further, our results suggest that low methylation of AGING cg14326354PRODH may potentially promote PRODH expression, further heighten autophagy to some extent [24], and then result in poor prognosis ( Figure 4). ...
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... senescent cells can promote reprogramming of tumor stem cells, increase cancer stemness, and accelerate tumor growth [30]. Thus, combined with our results, increased generation of senescent may be relevant to poor NSCLC prognosis for elderly patients (Figure 4). ...
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... by guaranteeing stability of the cellular proteome and proper organelle turnover, autophagy can prevent or slow down aging and extend lifespan [34]. The antagonistic effect exists between aging and the autophagy level resulting from low methylation of cg14326354PRODH, in spite of the harmful effect of both, which could provide a possible mechanism of the cg14326354PRODH-age interaction (Figure 4). ...
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... autophagy can act as a mechanism of tumor resistance to chemotherapy agents and lead to antagonistic effects of gefitinib combined with cisplatin in NSCLC treatment, which may contribute to poor therapeutic effectiveness and patient prognosis [22,23]. Further, our results suggest that low methylation of AGING cg14326354PRODH may potentially promote PRODH expression, further heighten autophagy to some extent [24], and then result in poor prognosis ( Figure 4). ...
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... senescent cells can promote reprogramming of tumor stem cells, increase cancer stemness, and accelerate tumor growth [30]. Thus, combined with our results, increased generation of senescent may be relevant to poor NSCLC prognosis for elderly patients (Figure 4). ...
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... by guaranteeing stability of the cellular proteome and proper organelle turnover, autophagy can prevent or slow down aging and extend lifespan [34]. The antagonistic effect exists between aging and the autophagy level resulting from low methylation of cg14326354PRODH, in spite of the harmful effect of both, which could provide a possible mechanism of the cg14326354PRODH-age interaction (Figure 4). ...
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Background
Sex is increasingly recognized as a significant factor contributing to the biological and clinical heterogeneity in AD. There is also growing evidence for the prominent role of DNA methylation (DNAm) in Alzheimer’s disease (AD).
Methods
We studied sex-specific DNA methylation differences in the blood samples of AD subjects compared to c...
Citations
... In epigenomewide methylation-age interaction analysis aimed to identify age-specific, prognosis-associated epigenetic biomarkers in NSCLC patients, PRODH promoter methylation was the only identified factor that interacted with age to affect prognosis. Indeed, low methylation of PRODH CpG island (where high levels of PRODH expression are expected) was proposed to benefit the survival of elderly lung ADC patients (age > 65 years), whereas it represented a negative prognostic factor for younger patients [40]. It is worth mentioning that senescence outcome also depends on age [39]. ...
Citation: Grossi, S.; Berno, E.; Chiofalo, P.; Chiaravalli, A.M.; Cinquetti, R.; Bruno, A.; Palano, M.T.; Gallazzi, M.; La Rosa, S.; Sessa, F.; et al. Proline Dehydrogenase (PRODH) Is Expressed in Lung Adenocarcinoma and Modulates Cell Survival and 3D Growth by Inducing Cellular Senescence. Int. J. Mol. Sci. 2024, 25, 714. https://doi. Abstract: The identification of markers for early diagnosis, prognosis, and improvement of therapeutic options represents an unmet clinical need to increase survival in Non-Small Cell Lung Cancer (NSCLC), a neoplasm still characterized by very high incidence and mortality. Here, we investigated whether proline dehydrogenase (PRODH), a mitochondrial flavoenzyme catalyzing the key step in proline degradation, played a role in NSCLC tumorigenesis. PRODH expression was investigated by immunohistochemistry; digital PCR, quantitative PCR, immunoblotting, measurement of reactive oxygen species (ROS), and functional cellular assays were carried out. PRODH expression was found in the majority of lung adenocarcinomas (ADCs). Patients with PRODH-positive tumors had better cancer-free specific and overall survival compared to those with negative tumors. Ectopic modulation of PRODH expression in NCI-H1299 and the other tested lung ADC cell lines decreased cell survival. Moreover, cell proliferation curves showed delayed growth in NCI-H1299, Calu-6 and A549 cell lines when PRODH-expressing clones were compared to control clones. The 3D growth in soft agar was also impaired in the presence of PRODH. PRODH increased reactive oxygen species production and induced cellular senescence in the NCI-H1299 cell line. This study supports a role of PRODH in decreasing survival and growth of lung ADC cells by inducing cellular senescence.
... a region often deleted in schizophrenia, and a cohort study revealed low methylation of PRODH benefitted the survival of elderly lung adenocarcinoma patients. [31][32][33] However, the cause of PRODH downregulation in MM is unknown. In this study, the sequencing data of 14 exons revealed that there is no gene mutation or DNA deletion of PRODH in MM cells. ...
Amino acids in the bone marrow microenvironment (BMME) are a critical factor for multiple myeloma (MM) progression. Here, we have determined that proline is elevated in BMME of MM patients and links to poor prognosis in MM. Moreover, exogenous proline regulates MM cell proliferation and drug resistance. Elevated proline in BMME is due to bone collagen degradation and abnormal expression of the key enzyme of proline catabolism, proline dehydrogenase (PRODH). PRODH is downregulated in MM patients, mainly as a result of promoter hypermethylation with high expression of DNMT3b. Thus, overexpression of PRODH suppresses cell proliferation and drug resistance of MM and exhibits therapeutic potential for treatment of MM. Altogether, we identify proline as a key metabolic regulator of MM, unveil PRODH governing MM progression and provide a promising therapeutic strategy for MM treatment.
... G × G interactions, as an essential element of personalized medicine, reflect that the effects of one gene on the disease outcome may vary across patients with different characteristics on another gene. Our previous studies have identified several epigenetic G × G interactions [10,11] and geneenvironment (G × E) interactions [12][13][14] relevant to NSCLC survival. However, these studies only focused on target genes that were identified in the literature. ...
Epigenome‐wide gene‐gene (G×G) interactions associated with non‐small cell lung cancer (NSCLC) survival may provide insights into molecular mechanisms and therapeutic targets. Hence, we proposed a three‐step analytic strategy to identify significant and robust G×G interactions that are relevant to NSCLC survival. In the first step, among 49 billion pairs of DNA methylation probes, we identified 175,775 G×G interactions with PBonferroni≤0.05 in the discovery phase of epigenomic analysis; among them, 15,534 were confirmed with P≤0.05 in the validation phase. In the second step, we further performed a functional validation for these G×G interactions at the gene expression level by way of a two‐phase (discovery and validation) transcriptomic analysis, and confirmed 25 significant G×G interactions enriched in the 6p21.33 and 6p22.1 regions. In the third step, we identified two G×G interactions using the trans‐omics analysis, which had significant (P≤0.05) epigenetic cis‐regulation of transcription and robust G×G interactions at both the epigenetic and transcriptional levels. These interactions were cg14391855×cg23937960 (βinteraction=0.018, P=1.87×10‐12), which mapped to RELA×HLA‐G (βinteraction=0.218, P=8.82×10‐11), and cg08872738×cg27077312 (βinteraction=‐0.010, P=1.16×10‐11), which mapped to TUBA1B×TOMM40 (βinteraction=‐0.250, P=3.83×10‐10). A trans‐omics mediation analysis revealed that 20.3% of epigenetic effects on NSCLC survival were significantly (P=0.034) mediated through transcriptional expression. These statistically significant trans‐omics G×G interactions can also discriminate patients with high risk of mortality. In summary, we identified two G×G interactions at both the epigenetic and transcriptional levels, and our findings may provide potential clues for precision treatment of NSCLC.
... Age is a well-recognized environmental risk factor for the progression of many cancers (11), including OSCC (12,13). Our previous gene-age interaction study of lung cancer revealed the reversed effects of PRODH DNA methylation on survival between young and elderly patients (14). Anyway, whether the effect of DNA methylation on OSCC survival varies with age remains largely unclear. ...
DNA methylation serves as a reversible and prognostic biomarker for oral squamous cell carcinoma (OSCC) patients. It is unclear whether the effect of DNA methylation on OSCC overall survival varies with age. As a result, we performed a two-phase gene–age interaction study of OSCC prognosis on an epigenome-wide scale using the Cox proportional hazards model. We identified one CpG probe, cg11676291MORN1 , whose effect was significantly modified by age (HRdiscovery = 1.018, p = 4.07 × 10⁻⁰⁷, FDR-q = 3.67 × 10⁻⁰²; HRvalidation = 1.058, p = 8.09 × 10⁻⁰³; HRcombined = 1.019, p = 7.36 × 10⁻¹⁰). Moreover, there was an antagonistic interaction between hypomethylation of cg11676291MORN1 and age (HRinteraction = 0.284; 95% CI, 0.135–0.597; p = 9.04 × 10⁻⁰⁴). The prognosis of OSCC patients was well discriminated by the prognostic score incorporating cg11676291MORN1 –age interaction (HRhigh vs. low = 3.66, 95% CI: 2.40–5.60, p = 1.93 × 10⁻⁰⁹). By adding 24 significant gene–age interactions using a looser criterion, we significantly improved the area under the receiver operating characteristic curve (AUC) of the model at 3- and 5-year prognostic prediction (AUC3-year = 0.80, AUC5-year = 0.79, C-index = 0.75). Our study identified a significant interaction between cg11676291MORN1 and age on OSCC survival, providing a potential therapeutic target for OSCC patients.
... As is well known, gene-gene and gene-environment interactions provide important clues regarding biologic mechanisms of complex diseases [23] and are associated with the overall survival of NSCLC [10,11,14,22,24]. However, tumorigenesis and progression of complex diseases, such as NSCLC, often involves a multistep, multigenic, and multicausal biological process [25]; interactions between two relevant factors may only provide limited information understanding the cancer process driven by multiple factors [26]. ...
... Finally, prognostic models with three-way interactions substantially improved the prediction accuracy. It is known that gene-gene and gene-environment interactions on an epigenetic level play a crucial role in revealing biological mechanisms of complex diseases [23], including NSCLC [11,24]. Emerging evidence from higher-order interaction studies with high-throughput data [44,45] indicates that accommodation of such complex association patterns can improve the predictive power [46]. ...
The interaction between DNA methylation of tripartite motif containing 27 (cg05293407TRIM27 ) and smoking has previously been identified to reveal histologically heterogeneous effects of TRIM27 DNA methylation on early-stage non-small cell lung cancer (NSCLC) survival. However, to understand the complex mechanisms underlying NSCLC progression, we searched three-way interactions. A two-phase study was adopted to identify three-way interactions in the form of pack-year of smoking (number of cigarettes smoked per day × number of years smoked) × cg05293407TRIM27 × epigenome-wide DNA methylation CpG probe. Two CpG probes were identified with FDR-q≤0.05 in the discovery phase and P≤0.05 in the validation phase: cg00060500KIAA0226 and cg17479956EXT2 . Compared to a prediction model with only clinical information, the model added 42 significant three-way interactions using a looser criterion (discovery: FDR-q≤0.10, validation: P≤0.05), had substantially improved the area under the receiver operating characteristic curve (AUC) of the prognostic prediction model for both 3-year and 5-year survival. Our research identified the complex interaction effects among multiple environment and epigenetic factors, and provided therapeutic target for NSCLC patients.
Long noncoding RNA (lncRNA) are involved in regulating physiological behaviors for various malignant tumors, including non-small-cell lung cancer (NSCLC). However, few studies comprehensively evaluated both lncRNA–lncRNA interaction effects and main effects of lncRNA on overall survival of NSCLC. Hence, we performed a two-phase designed study of lncRNA expression in tumor tissues using 604 NSCLC patients from The Cancer Genome Atlas as the discovery phase and 839 patients from Gene Expression Omnibus as the validation phase. In the discovery phase, we adopted a two-step strategy, Screening before Testing , for dimension reduction and signal detection. These candidate lncRNAs first screened out by the weighted random forest (Ranger), were then tested through the Cox proportional hazards model adjusted for covariates. Significant lncRNAs with either type of effects aforementioned were carried forward into the validation phase to confirm their significances again. As a result, in the discovery phase, 19 lncRNAs were identified by Ranger, among which five lncRNAs and one pair of lncRNA–lncRNA interaction exhibited significant effects (FDR- q ≤ 0.05) main and interaction effects on NSCLC survival, respectively, through Cox model. After the independent validation, we finally observed that one lncRNA (ENSG00000227403.1) with main effect was robustly associated with NSCLC prognosis ( HR discovery = 0.90, P = 1.20 × 10 –3 ; HR validation = 0.94, P = 4.11 × 10 –3 ) and one pair of lncRNAs (ENSG00000267121.4 and ENSG00000272369.1) had significant interaction effect on NSCLC survival ( HR discovery = 1.12, P = 3.07 × 10 –4 ; HR validation = 1.11, P = 0.0397). Our comprehensive NSCLC prognostic study of lncRNA provided population-level evidence for further functional study.
L-proline catabolism is emerging as a key pathway that is critical to cellular metabolism, growth, survival, and death. Proline dehydrogenase (PRODH) enzyme, which catalyzes the first step of proline catabolism, has diverse functional roles in regulating many pathophysiological processes, including apoptosis, autophagy, cell senescence, and cancer metastasis. Notably, accumulated evidence demonstrated that PRODH plays complex role in many types of cancers. In this review, we briefly introduce the function of PRODH, then its expression in different types of cancer. We next discuss the regulation of PRODH in cancer, the downstream pathways of PRODH and the therapies that are under investigation. Finally, we propose novel insights for future perspectives on the modulation of PRODH.
