The modulatory role of Sirtuins in FOXP3 expression and Treg differentiation is reviewed, providing insight into their contribution to tumor immunosuppression and integrating network-based analysis identified miR-34a as a central regulator and validated the miRNA-Transcription Factor-Sirtuin axis as a viable framework for cancer therapeutic targeting.
Sirtuins (SIRT1-SIRT7) are a family of NAD+-dependent lysine deacetylases that possess mono-ADP-ribosyltransferase activity and integrate cellular metabolic status with chromatin regulation, genome maintenance, redox homeostasis, immune responses, and adaptation to cancer therapies. Their translational value has been obscured by a recurring paradox: the same isoform may constrain malignant transformation in one setting yet support metastatic competence, stemness, immune evasion, or drug resistance in another. This review reframes that paradox as a measurable problem of context. We define a SIRT context code in which NAD+ availability and compartmentalization, subcellular localization, PTM state, chromatin occupancy, oncogenic genotype, cell lineage, and tumor microenvironment jointly determine sirtuin output. Using recent mechanistic and translational evidence, we summarize how sirtuins regulate metabolic switching, histone acetylation and lactylation, genome stability, cancer-associated fibroblast programs, regulatory T-cell enrichment, cancer stem-cell plasticity, angiogenesis, and resistance to DNA-damaging, targeted, and immune therapies. We further argue that successful sirtuin pharmacology will require context matching rather than indiscriminate activation or inhibition. Priorities include spatial and single-cell biomarker discovery, compartment-specific NAD+ measurements, PTM-resolved activity assays, structure-guided isoform-selective agents, and degrader strategies targeting non-catalytic scaffolding functions. Sirtuins should therefore be viewed as metabolic-epigenetic decision nodes rather than fixed oncogenes or tumor suppressors. However, the evidence remains predominantly preclinical, and our search identified no clinical-stage oncology trials of direct sirtuin modulators using prospective biomarker stratification, underscoring that this framework remains translationally aspirational rather than clinically validated.
Abdelwahab Aly, Zhiqing Tan, S. Sasidharan et al.· Critical reviews in oncology...· 0 citations
Sirtuins (SIRT1–SIRT7) are nicotinamide adenine dinucleotide (NAD+) dependent deacylases that serves as metabolic sensors, coupling cellular energy status to chromatin structure, mitochondrial function, and stress responses. Dysregulated SIRT activity has been extensively studied in aging, metabolic syndrome, cardiovascular disease, neurodegeneration, cancer, and immune disorders. However, robust human evidence and SIRT‐targeted therapies are lacking. Transgenic mouse models serve as key platforms to study gene function and guide therapeutic development. This review synthesizes evidence from Sirt1–7 transgenic mouse models regarding the core cellular processes governed by SIRTs: metabolism, genome integrity, stress resistance, immunity, and autophagy, and illustrates their operation across different organ systems. By comparing global, tissue‐specific, and inducible knockout (KO) and overexpression (OE) models of cardiovascular, respiratory, digestive, nervous, endocrine, urogenital, musculoskeletal, malignant, and immune diseases, we identified central regulatory SIRTs (SIRT1, SIRT3, and SIRT6), context‐dependent modifiers (SIRT2, SIRT4, SIRT5, and SIRT7), and their organ‐ and cell type‐specific functions. We also summarize representative small‐molecule SIRT activators, inhibitors, and degraders, covering both clinical and preclinical studies, and highlight where contradictions and knowledge gaps remain. Together, these analyses help clarify which aspects of SIRT modulation are most promising and under what isoform, tissue, and disease contexts they should be pursued for the development of SIRT‑targeted therapies in human disease.
The sirtuin family proteins SIRT5 and SIRT7, as NAD⁺-dependent lysine desuccinylases, exert critical yet context-dependent roles in cancer progression. Mitochondrial SIRT5 functions as a metabolic rheostat, desuccinylating key enzymes in the TCA cycle, glutaminolysis, and fatty acid oxidation to maintain redox balance and bioenergetic output. Conversely, nuclear SIRT7 acts as an epigenetic modulator, regulating chromatin architecture and DNA damage repair via histone and non-histone desuccinylation. These compartmentalized activities converge to coordinate a metabolic-epigenetic axis that drives tumor adaptation to metabolic stress, evasion of immune surveillance, and therapeutic resistance. Given this functional duality, biomarker-guided therapeutic strategies are imperative. This review synthesizes the emerging roles of SIRT5/7-mediated desuccinylation in cancer metabolism, immunity, and drug resistance, highlighting their potential as targets for synergistic metabolic-immunotherapy interventions.
P. Luo, Xinghua Long· Biochemical Pharmacology· 0 citations
DExH-box helicase 9 (DHX9) is a multifunctional nucleic acid helicase that participates in R-loop homeostasis, genome maintenance, RNA metabolism, and innate immune signaling. Accumulating evidence has linked aberrant DHX9 expression or activity to tumorigenesis, tumor progression, treatment response, and patient prognosis. However, its role in cancer is highly context-dependent, rather than uniformly oncogenic or tumor suppressive. Depending on its molecular partners, subcellular localization, post-translational modifications, tumor genotype, and immune microenvironment, DHX9 may either promote malignant phenotypes or contribute to tumor-restraining processes. In this review, we summarize the molecular characteristics and regulatory properties of DHX9, discuss its roles in genome stability, transcriptional and post-transcriptional control, circular RNA (circRNA) biogenesis, and tumor-immune crosstalk, and evaluate its emerging value as a potential biomarker and therapeutic target. We also highlight key challenges in this field, including mechanistic heterogeneity, insufficient translational validation, and the urgent need for context-informed patient stratification to maximize the clinical utility of DHX9-targeted strategies.
Yejin Cai, Ziyuan Chen, Jiaying Xiong et al.· Biochimica et biophysica act...· 0 citations
The ubiquitin-proteasome system (UPS) is an important regulator of numerous cellular pathways, including DNA repair, protein degradation, the cell cycle, and signal transduction. UBE2C, a member of the ubiquitin-conjugating enzyme family, facilitates the ubiquitination of essential cellular regulators. Notably, UBE2C is consistently overexpressed in breast, lung, brain, hepatocellular, and ovarian carcinomas. Increased UBE2C expression is associated with tumour aggressiveness, genomic instability, epithelial-to-mesenchymal transition, and resistance to chemotherapy and radiotherapy. Our review explores the mechanistic involvement of UBE2C in diverse cancers, with a particular focus on its involvement in DNA damage repair mediated by the anaphase-promoting complex (APC/C). Furthermore, the regulatory effects of miR-381, miR-503, and miR-205 on UBE2C expression were examined, highlighting the promising prospects of these miRNAs for targeted cancer therapy. The involvement of UBE2C in different cancer hallmarks underscores its potential as a biomarker and therapeutic target. A comprehensive understanding of its mechanistic involvement in cell cycle regulation and DNA repair will further enhance its application in diagnostics, personalised medicine, and precision medicine.
SIRT3 is a mitochondria-localized member of the sirtuin family, playing a key role in cellular antioxidant defense. Its function in carcinogenesis and therapy response remains uncertain. In the present study, we sought to identify the role of SIRT3 in regulating cell death induced by conventional DNA-damaging anticancer drugs or mitochondria-targeting compounds using bioinformatic analysis, western blot analysis, viability, and clonogenic assays. High SIRT3 levels were associated with higher sensitivity to DNA-damaging cisplatin and resistance to mitochondria-targeted α-tocopheryl succinate (α-TOS) in non-small cell lung cancer, ovarian cancer, and neuroblastoma cells. SIRT3 overexpression, knockout, or knockdown did not influence the sensitivity of cancer cells to cisplatin. SIRT3 depletion in cells with high basal SIRT3 levels decreased the viability and clonogenic capacity of cells after α-TOS treatment without triggering apoptosis. SIRT3 overexpression in cells with low basal SIRT3 levels increased viability and decreased accumulation of apoptotic markers after α-TOS treatment. Collectively, our data demonstrate that SIRT3 does not play a major role in cancer cell death induced by the conventional chemotherapeutic drug cisplatin but exerts a protective role in the case of the mitochondria-targeting agent α-TOS.
M. A. Yapryntseva, Matvey A. Vinogradov, P. I. Volik et al.· Cell Communication and Signa...· 0 citations