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Clinical Cancer Research
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X- and Y-Linked Chromatin-Modifying Genes as Regulators of Sex-Specific Cancer Incidence and Prognosis

Rossella Tricarico, Emmanuelle Nicolas, Michael J. Hall and Erica A. Golemis
Rossella Tricarico
1Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
2Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.
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  • For correspondence: Erica.Golemis@fccc.edu Rossella.Tricarico@fccc.edu
Emmanuelle Nicolas
1Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
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Michael J. Hall
3Cancer Prevention and Control Program, Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
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Erica A. Golemis
1Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
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  • ORCID record for Erica A. Golemis
  • For correspondence: Erica.Golemis@fccc.edu Rossella.Tricarico@fccc.edu
DOI: 10.1158/1078-0432.CCR-20-1741 Published November 2020
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Abstract

Biological sex profoundly conditions organismal development and physiology, imposing wide-ranging effects on cell signaling, metabolism, and immune response. These effects arise from sex-specified differences in hormonal exposure, and from intrinsic genetic and epigenetic differences associated with the presence of an XX versus XY chromosomal complement. In addition, biological sex is now recognized to be a determinant of the incidence, presentation, and therapeutic response of multiple forms of cancer, including cancers not specifically associated with male or female anatomy. Although multiple factors contribute to sex-based differences in cancer, a growing body of research emphasizes a role for differential activity of X- and Y-linked tumor-suppressor genes in males and females. Among these, the X-linked KDM6A/UTX and KDM5C/JARID1C/SMCX, and their Y-linked paralogs UTY/KDM6C and KDM5D/JARID1D/SMCY encode lysine demethylases. These epigenetic modulators profoundly influence gene expression, based on enzymatic activity in demethylating H3K27me3 and H3K4me3, and nonenzymatic scaffolding roles for large complexes that open and close chromatin for transcription. In a growing number of cases, mutations affecting these proteins have been recognized to strongly influence cancer risk, prognosis, and response to specific therapies. However, sex-specific patterns of mutation, expression, and activity of these genes, coupled with tissue-specific requirement for their function as tumor suppressors, together exemplify the complex relationship between sex and cancer vulnerabilities. In this review, we summarize and discuss the current state of the literature on the roles of these proteins in contributing to sex bias in cancer, and the status of clinical agents relevant to their function.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2020;26:5567–78

  • Received May 6, 2020.
  • Revision received June 24, 2020.
  • Accepted July 27, 2020.
  • Published first July 30, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 26 (21)
November 2020
Volume 26, Issue 21
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X- and Y-Linked Chromatin-Modifying Genes as Regulators of Sex-Specific Cancer Incidence and Prognosis
Rossella Tricarico, Emmanuelle Nicolas, Michael J. Hall and Erica A. Golemis
Clin Cancer Res November 1 2020 (26) (21) 5567-5578; DOI: 10.1158/1078-0432.CCR-20-1741

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X- and Y-Linked Chromatin-Modifying Genes as Regulators of Sex-Specific Cancer Incidence and Prognosis
Rossella Tricarico, Emmanuelle Nicolas, Michael J. Hall and Erica A. Golemis
Clin Cancer Res November 1 2020 (26) (21) 5567-5578; DOI: 10.1158/1078-0432.CCR-20-1741
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  • Article
    • Abstract
    • Introduction
    • Tumor-Suppressive Chromatin Modifiers on the X and Y Chromosomes
    • The KDM5 and KDM6 Protein Families
    • Targeting Histone Modifications
    • Future Prospects
    • Disclosure of Potential Conflicts of Interest
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