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P53 as a hub in cellular redox regulation and therapeutic target in cancer.

ABSTRACT: The TP53 tumor suppressor gene encodes a DNA-binding transcription factor that regulates multiple cellular processes including cell growth and cell death. The ability of p53 to bind to DNA and activate transcription is tightly regulated by post-translational modifications and is dependent on a reducing cellular environment. Some p53 transcriptional target genes are involved in regulation of the cellular redox homeostasis, e.g. TIGAR and GLS2. A large fraction of human tumors carry TP53 mutations, most commonly missense mutations that lead to single amino acid substitutions in the core domain. Mutant p53 proteins can acquire so called gain-of-function activities and influence the cellular redox balance in various ways, for instance by binding of the Nrf2 transcription factor, a major regulator of cellular redox state. The DNA-binding core domain of p53 has 10 cysteine residues, three of which participate in holding a zinc atom that is critical for p53 structure and function. Several novel compounds that refold and reactivate missense mutant p53 bind to specific p53 cysteine residues. These compounds can also react with other thiols and target components of the cellular redox system, such as glutathione. Dual targeting of mutant p53 and redox homeostasis may allow more efficient treatment of cancer.

SUBMITTER: Eriksson SE

PROVIDER: S-EPMC6734141 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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p53 as a hub in cellular redox regulation and therapeutic target in cancer.

Eriksson Sofi E SE Ceder Sophia S Bykov Vladimir J N VJN Wiman Klas G KG

Journal of molecular cell biology 20190401 4

The TP53 tumor suppressor gene encodes a DNA-binding transcription factor that regulates multiple cellular processes including cell growth and cell death. The ability of p53 to bind to DNA and activate transcription is tightly regulated by post-translational modifications and is dependent on a reducing cellular environment. Some p53 transcriptional target genes are involved in regulation of the cellular redox homeostasis, e.g. TIGAR and GLS2. A large fraction of human tumors carry TP53 mutations ...[more]

PMID: 30892598

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Project description:ObjectiveBladder cancer is a clinical and social conundrum due to its high incidence and recurrence rate. It is urgent to find new targets for the diagnosis and treatment of bladder cancer and improve the prognosis and survival rate of bladder cancer patients. We sought a prognosis-related gene, built related models of evaluated bladder cancer and identified the function of the hub gene in bladder cancer.MethodsWe downloaded the data of bladder cancer patients from the TCGA database, and used differentially expressed genes (DEGs), copy number variation (CNV) and survival analysis to scan the hub genes associated with prognosis in bladder cancer. Then, multi-factor cox regression was used to obtain the bladder cancer prognosis correlation model. Then, we analyzed the relationship between the expression of hub gene and immune microenvironment of bladder cancer. The relationship between the expression of hub gene and prognosis in bladder cancer patients was verified by immunohistochemistry. Cell proliferation assay and drug sensitivity test in vivo were used to verify the inhibition of bladder cancer by targeted inhibitors.ResultsIn bladder cancer, we screened seven hub genes (ACLY, CNP, NKIRAS2, P3H4, PDIA6, VPS25 and XPO1) associated with survival. Moreover, the multifactor regression model constructed with hub gene can well distinguish the prognosis of bladder cancer. Hub gene is mostly associated with immune microenvironment. Immunohistochemical results basically confirmed the importance of XPO1 in bladder cancer. Selinexor (an inhibitor of XPO1) could effectively inhibit the proliferation of bladder cancer in the cell proliferation experiments by CCK-8 assays and it could suppress the growth of bladder cancer in mouse bladder cancer model.ConclusionsIn this study, a prognostic model with seven hub genes has provided great help for the prognosis prediction of bladder cancer patients. And XPO1 is an important target affecting the prognosis of bladder cancer, and inhibition of XPO1 can effectively inhibit bladder cancer proliferation and growth.

Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) remains a major challenge in cancer medicine and is characterized by a 5-year survival rate of <10%. Compelling evidence suggests that the devastating disease outcome of PDAC patients is linked to a high degree of intra- and interindividual tumor heterogeneity, which is predominantly installed at the level of gene transcription. The cellular and molecular complexities of the disease explain the poor efficacy of "one-size-fits-all" therapeutic approaches in PDAC treatment and strongly argue for pursuing tailored therapeutic strategies to tackle PDAC. In a highly dynamic manner, a network of transcription factors and epigenetic regulatory proteins temporally and spatially control the diverse transcriptomic states determining PDAC heterogeneity. Given the reversibility of epigenetic processes, pharmacological intervention with key epigenetic drivers of PDAC heterogeneity appeals as a promising concept to shift the transcriptomic phenotype of PDAC toward a less aggressive and more chemosensible state.SummaryIn this review, we discuss the chances and pitfalls of epigenetic treatment strategies in overcoming and shifting molecular and cellular PDAC heterogeneities in order to combat PDAC. To this end, we utilized the keywords "pancreatic cancer," "heterogeneity," and "epigenetics" to search for relevant articles on the database PubMed and selected interventional studies enrolling PDAC patients as displayed in clinicaltrails.gov to generate a synopsis of clinical trials involving epigenetic targeting.Key messagesTargeting epigenetic regulators in PDAC represents a promising concept to reprogram molecular and cellular tumor heterogeneities in the pancreas and hence to modulate the PDAC phenotype in favor of a less aggressive and more therapy susceptible disease course. However, we just start to understand the complex interactions of epigenetic regulators in controlling PDAC plasticity, and a clinical breakthrough utilizing epigenetic targeting in PDAC patients has not been achieved yet. Nevertheless, increasing translational efforts which consider the pleiotropic effects of targeting epigenetic regulation in different cellular compartments of the tumor and that focus on the utility and sequence of combinatory treatment approaches might pave the way toward novel epigenetic treatment strategies in PDAC therapy.

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P53 as a hub in cellular redox regulation and therapeutic target in cancer.

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p53 as a hub in cellular redox regulation and therapeutic target in cancer.

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