-
1.
Unveiling the methionine cycle: a key metabolic signature and NR4A2 as a methionine-responsive oncogene in esophageal squamous cell carcinoma.
Jin, X, Liu, L, Liu, D, Wu, J, Wang, C, Wang, S, Wang, F, Yu, G, Jin, X, Xue, YW, et al
Cell death and differentiation. 2024
Abstract
Esophageal squamous cell carcinoma (ESCC) is a deadly malignancy with notable metabolic reprogramming, yet the pivotal metabolic feature driving ESCC progression remains elusive. Here, we show that methionine cycle exhibits robust activation in ESCC and is reversely associated with patient survival. ESCC cells readily harness exogenous methionine to generate S-adenosyl-methionine (SAM), thus promoting cell proliferation. Mechanistically, methionine augments METTL3-mediated RNA m6A methylation through SAM and revises gene expression. Integrative omics analysis highlights the potent influence of methionine/SAM on NR4A2 expression in a tumor-specific manner, mediated by the IGF2BP2-dependent stabilization of methylated NR4A2 mRNA. We demonstrate that NR4A2 facilitates ESCC growth and negatively impacts patient survival. We further identify celecoxib as an effective inhibitor of NR4A2, offering promise as a new anti-ESCC agent. In summary, our findings underscore the active methionine cycle as a critical metabolic characteristic in ESCC, and pinpoint NR4A2 as a novel methionine-responsive oncogene, thereby presenting a compelling target potentially superior to methionine restriction.
-
2.
The impact of toxic metal bioaccumulation on colorectal cancer: Unravelling the unexplored connection.
Bonfiglio, R, Sisto, R, Casciardi, S, Palumbo, V, Scioli, MP, Palumbo, A, Trivigno, D, Giacobbi, E, Servadei, F, Melino, G, et al
The Science of the total environment. 2024;:167667
Abstract
Colorectal cancer is a major public health concern, with increasing incidence and mortality rates worldwide. Environmental factors, including exposure to toxic metals, such as lead, chromium, cadmium, aluminium, copper, arsenic and mercury, have been suggested to play a significant role in the development and progression of this neoplasia. In particular, the bioaccumulation of toxic metals can play a significant role in colorectal cancer by regulating biological phenomenon associated to both cancer occurrence and progression, such as cell death and proliferation. Also, frequently these metals can induce DNA mutations in well-known oncogenes. This review provides a critical analysis of the current evidence, highlighting the need for further research to fully grasp the complex interplay between toxic metal bioaccumulation and colorectal cancer. Understanding the contribution of toxic metals to colorectal cancer occurrence and progression is essential for the development of targeted preventive strategies and social interventions, with the ultimate goal of reducing the burden of this disease.
-
3.
p63 orchestrates serine and one carbon metabolism enzymes expression in head and neck cancer.
Cappello, A, Tosetti, G, Smirnov, A, Ganini, C, Yang, X, Shi, Y, Wang, Y, Melino, G, Bernassola, F, Candi, E
Biology direct. 2023;(1):73
Abstract
BACKGROUND Head and neck squamous cell carcinoma (HNSCC) is characterized by high proliferation and limited differentiation. The altered expression of the p53 family members, and specifically of p63, represents a pivotal event in the pathogenesis of HNSCC. Physiologically, p63 affects metabolism through the direct transactivation of the enzyme hexokinase 2, and subsequently controls the proliferation of epithelial cells; nonetheless, its role in cancer metabolism is still largely unclear. The high energetic demand of cancer and the consequent needs of a metabolic reshape, also involve the serine and glycine catabolic and anabolic pathways, including the one carbon metabolism (OCM), to produce energetic compounds (purines) and to maintain cellular homeostasis (glutathione and S-adenosylmethionine). RESULTS The involvement in serine/glycine starvation by other p53 family members has been reported, including HNSCC. Here, we show that in HNSCC p63 controls the expression of the enzymes regulating the serine biosynthesis and one carbon metabolism. p63 binds the promoter region of genes involved in the serine biosynthesis as well as in the one carbon metabolism. p63 silencing in a HNSCC cell line affects the mRNA and protein levels of these selected enzymes. Moreover, the higher expression of TP63 and its target enzymes, negatively impacts on the overall survival of HNSCC patients. CONCLUSION These data indicate a direct role of p63 in the metabolic regulation of HNSCC with significant clinical effects.
-
4.
Orchestration of Mesenchymal Stem/Stromal Cells and Inflammation During Wound Healing.
Zhu, M, Cao, L, Melino, S, Candi, E, Wang, Y, Shao, C, Melino, G, Shi, Y, Chen, X
Stem cells translational medicine. 2023;(9):576-587
-
-
Free full text
-
Abstract
Wound healing is a complex process and encompasses a number of overlapping phases, during which coordinated inflammatory responses following tissue injury play dominant roles in triggering evolutionarily highly conserved principals governing tissue repair and regeneration. Among all nonimmune cells involved in the process, mesenchymal stem/stromal cells (MSCs) are most intensely investigated and have been shown to play fundamental roles in orchestrating wound healing and regeneration through interaction with the ordered inflammatory processes. Despite recent progress and encouraging results, an informed view of the scope of this evolutionarily conserved biological process requires a clear understanding of the dynamic interplay between MSCs and the immune systems in the process of wound healing. In this review, we outline current insights into the ways in which MSCs sense and modulate inflammation undergoing the process of wound healing, highlighting the central role of neutrophils, macrophages, and T cells during the interaction. We also draw attention to the specific effects of MSC-based therapy on different pathological wound healing. Finally, we discuss how ongoing scientific advances in MSCs could be efficiently translated into clinical strategies, focusing on the current limitations and gaps that remain to be overcome for achieving preferred functional tissue regeneration.
-
5.
p63: a crucial player in epithelial stemness regulation.
Li, Y, Giovannini, S, Wang, T, Fang, J, Li, P, Shao, C, Wang, Y, , , Shi, Y, Candi, E, et al
Oncogene. 2023;(46):3371-3384
-
-
Free full text
-
Abstract
Epithelial tissue homeostasis is closely associated with the self-renewal and differentiation behaviors of epithelial stem cells (ESCs). p63, a well-known marker of ESCs, is an indispensable factor for their biological activities during epithelial development. The diversity of p63 isoforms expressed in distinct tissues allows this transcription factor to have a wide array of effects. p63 coordinates the transcription of genes involved in cell survival, stem cell self-renewal, migration, differentiation, and epithelial-to-mesenchymal transition. Through the regulation of these biological processes, p63 contributes to, not only normal epithelial development, but also epithelium-derived cancer pathogenesis. In this review, we provide an overview of the role of p63 in epithelial stemness regulation, including self-renewal, differentiation, proliferation, and senescence. We describe the differential expression of TAp63 and ΔNp63 isoforms and their distinct functional activities in normal epithelial tissues and in epithelium-derived tumors. Furthermore, we summarize the signaling cascades modulating the TAp63 and ΔNp63 isoforms as well as their downstream pathways in stemness regulation.
-
6.
Metabolic regulation by p53 prevents R-loop-associated genomic instability.
Panatta, E, Butera, A, Mammarella, E, Pitolli, C, Mauriello, A, Leist, M, Knight, RA, Melino, G, Amelio, I
Cell reports. 2022;(5):111568
Abstract
Gene-environment interactions can perturb the epigenome, triggering network alterations that participate in cancer pathogenesis. Integrating epigenomics, transcriptomics, and metabolic analyses with functional perturbation, we show that the tumor suppressor p53 preserves genomic integrity by empowering adequate levels of the universal methyl donor S-adenosylmethionine (SAM). In p53-deficient cells, perturbation of DNA methylation promotes derepression of heterochromatin, massive loss of histone H3-lysine 9 methylation, and consequent upregulation of satellite RNAs that triggers R-loop-associated replication stress and chromosomal aberrations. In p53-deficient cells, the inadequate SAM level underlies the inability to respond to perturbation because exogenous reintroduction of SAM represses satellite elements and restores the ability to cope with stress. Mechanistically, p53 transcriptionally controls genes involved in one-carbon metabolism, including Slc43a2, the methionine uptake transporter that is critical for SAM synthesis. Supported by clinical data, our findings shed light on the role of p53-mediated metabolism in preventing unscheduled R-loop-associated genomic instability.
-
7.
Immune response in COVID-19: what is next?
Li, Q, Wang, Y, Sun, Q, Knopf, J, Herrmann, M, Lin, L, Jiang, J, Shao, C, Li, P, He, X, et al
Cell death and differentiation. 2022;(6):1107-1122
-
-
Free full text
-
Abstract
The coronavirus disease 2019 (COVID-19) has been a global pandemic for more than 2 years and it still impacts our daily lifestyle and quality in unprecedented ways. A better understanding of immunity and its regulation in response to SARS-CoV-2 infection is urgently needed. Based on the current literature, we review here the various virus mutations and the evolving disease manifestations along with the alterations of immune responses with specific focuses on the innate immune response, neutrophil extracellular traps, humoral immunity, and cellular immunity. Different types of vaccines were compared and analyzed based on their unique properties to elicit specific immunity. Various therapeutic strategies such as antibody, anti-viral medications and inflammation control were discussed. We predict that with the available and continuously emerging new technologies, more powerful vaccines and administration schedules, more effective medications and better public health measures, the COVID-19 pandemic will be under control in the near future.
-
8.
Metabolism-Based Molecular Subtyping Endows Effective Ketogenic Therapy in p53-Mutant Colon Cancer.
Tang, M, Xu, H, Huang, H, Kuang, H, Wang, C, Li, Q, Zhang, X, Ge, Y, Song, M, Zhang, X, et al
Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2022;(29):e2201992
Abstract
Although targeting cancer metabolism is a promising therapeutic strategy, clinical success depends on accurate molecular and metabolic subtyping. Here, this study reports two metabolism-based molecular subtypes associated with the ketogenic treatment of colon cancer: glycolytic (glycolysis+ /ketolysis- ) and ketolytic (glycolysis+ /ketolysis+ ), which are manifested by distinct profiles of metabolic enzymes and mitochondrial dysfunction, and by different responses to ketone-containing interventions in vitro and in vivo. Notably, the glycolytic subtype is able to be transformed into the ketolytic subtype in p53-mutated tumors upon glucose limitation, rendering resistance to ketogenic therapy associated with upregulation of ketolytic enzymes, such as OXCT1 by mutant p53. The allosteric activator of mutant p53 effectively blocks the rewired molecular expression and the reprogrammed metabolism, leading to the suppression of tumor growth. The findings highlight the utility of metabolic subtyping to guide ketogenic therapy in colon cancer and identify mutant p53 as a synthetic lethality target for ketogenic treatment.
-
9.
p63 in corneal and epidermal differentiation.
Novelli, F, Ganini, C, Melino, G, Nucci, C, Han, Y, Shi, Y, Wang, Y, Candi, E
Biochemical and biophysical research communications. 2022;:15-22
Abstract
The transcription factor p63, belonging to the p53 family, is considered the master regulator of epidermal differentiation, skin, and in general of the differentiation of ectodermal tissues. Mutations in TP63 gene cause several rare ectodermal dysplasia disorders that refers to epidermal structural abnormalities and ocular surface disease, such as Ectrodactyly Ectodermal Dysplasia Clefting (EEC) syndrome. In this review, we discuss the key roles of p63 in keratinocytes and corneal epithelial differentiation, highlighting the function of the ΔNp63α isoform in driving limbal stem cell and epithelial stem cells commitment. We have summarized the specific ocular phenotypes observed in the TP63-mutation derived EEC syndrome, discussing the current and novel therapeutic strategies for the management of the ocular manifestations in EEC syndrome.
-
10.
Actively or passively deacidified lysosomes push β-coronavirus egress.
Wang, X, Melino, G, Shi, Y
Cell death & disease. 2021;(3):235