Traditionally, cancer has been viewed as a set of diseases that are driven by the accumulation of genetic mutations, but we now understand that disruptions in epigenetic regulatory mechanisms are prevalent in cancer as well. Unlike genetic mutations, however, epigenetic alterations are reversible, making them desirable therapeutic targets. The potential for diet, and bioactive dietary components, to target epigenetic pathways in cancer is now widely appreciated, but our understanding of how to utilize these compounds for effective chemopreventive strategies in humans is in its infancy. This review provides a brief overview of epigenetic regulation and the clinical applications of epigenetics in cancer. It then describes the capacity for dietary components to contribute to epigenetic regulation, with a focus on the efficacy of dietary epigenetic regulators as secondary cancer prevention strategies in humans. Lastly, it discusses the necessary precautions and challenges that will need to be overcome before the chemopreventive power of dietary-based intervention strategies can be fully harnessed.
The most commonly mutated gene in all human cancers is the tumor suppressor gene TP53; however, in addition to the loss of tumor suppressor functions, mutations in TP53 can also promote cancer progression by altering cellular iron acquisition and metabolism. The primary objective of this work was to determine how TP53 mutation status influences the molecular control of iron homeostasis. The effect of TP53 mutation type on cellular iron homeostasis was examined using cell lines with inducible versions of either wild-type TP53 or a representative mutated TP53 gene from exemplary “hotspot” mutations in the DNA binding domain (R248, R273, and R175) as well as H193Y. The introduction of distinct TP53 mutation types alone was sufficient to disrupt cellular iron metabolism. These effects were mediated, at least in part, due to differences in the responsiveness of iron regulatory proteins (IRPs) to cellular iron availability. IRPs are considered the master regulators of intracellular iron homeostasis because they coordinate the expression of iron storage (ferritin) and iron uptake (transferrin receptor) genes. In response to changes in iron availability, cells harboring either a wild-type TP53 or R273H TP53 mutation displayed canonical IRP-mediated responses, but neither IRP1 RNA binding activity nor IRP2 protein levels were affected by changes in iron status in cells harboring the R175H mutation type. However, all mutation types exhibited robust changes in ferritin and transferrin receptor protein expression in response to iron loading and iron chelation, respectively. These findings suggest a novel, IRP-independent mode of iron regulation in cells expressing distinct TP53 mutations. As TP53 is mutated in nearly half of all human cancers, and iron is necessary for cancer cell growth and proliferation, the studies have implications for a wide range of clinically important cancers.
The most commonly mutated gene in all human cancers is the tumor suppressor gene p53, but in addition to loss of tumor suppressor functions, mutations in p53 can also promote cancer progression by altering cellular iron acquisition and metabolism. The primary objective of this work was to determine how p53 mutation status influences the molecular control of iron homeostasis. Though hundreds of p53 mutations have been identified, the majority occur within the DNA binding domain and can be subdivided into two broad classes: contact (e.g., R273H) or conformational (e.g., R175H). By generating cell lines with inducible versions of some of the most common conformational and contact-type p53 mutations we have established that introduction of specific p53 mutation types alone is sufficient to disrupt cellular iron metabolism. We also demonstrate these effects are mediated at least in part due to differences in the responsiveness of Iron Regulatory Proteins (IRP) to cellular iron availability. IRP are considered the master regulators of intracellular iron homeostasis because they coordinate the expression of iron storage (ferritin) and iron uptake (transferrin receptor) genes. In response to changes in iron availability cells harboring either a wild-type p53 or contact (R273H) p53 mutation display canonical IRP-mediated responses, but neither IRP1 RNA binding activity nor IRP2 protein levels are affected by changes in iron status in cells harboring the conformational type mutant (R175H). Yet, both contact and conformational mutants exhibit robust changes in ferritin and transferrin receptor protein expression in response to iron loading and iron chelation, respectively. These findings suggest a novel, IRP-independent mode of iron regulation in cells expressing conformational type p53 mutants. Preliminary proteomics data suggests that lack of IRP responsiveness in cells expressing conformational p53 mutations may result from impaired iron-sulfur cluster biogenesis. These findings are currently being explored as a means of exploiting distinct p53 mutation types to more favorably induce iron-mediated cell death via the activation of ferroptosis. As p53 is mutated in nearly half of all human cancers, and iron is necessary for cancer cell growth and proliferation, the studies have implications for a wide range of clinically important cancers. Citation Format: Eshan Dandekar, Aishwarya Srinivasan, Stephen Clarke, Mckale Montgomery. Induction of distinct p53 mutation types differentially influences the control of cellular iron metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4365.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.