Biology and targeting of the Jumonji-domain histone demethylase family in childhood neoplasia: a preclinical overview

ABSTRACT

Introduction: Epigenetic mechanisms of gene regulatory control play fundamental roles in developmental morphogenesis, and, as more recently appreciated, are heavily implicated in the onset and progression of neoplastic disease, including cancer. Many epigenetic mechanisms are therapeutically targetable, providing additional incentive for understanding of their contribution to cancer and other types of neoplasia.

Areas covered: The Jumonji-domain histone demethylase (JHDM) family exemplifies many of the above traits. This review summarizes the current state of knowledge of the functions and pharmacologic targeting of JHDMs in cancer and other neoplastic processes, with an emphasis on diseases affecting the pediatric population.

Expert opinion: To date, the JHDM family has largely been studied in the context of normal development and adult cancers. In contrast, comparatively few studies have addressed JHDM biology in cancer and other neoplastic diseases of childhood, especially solid (non-hematopoietic) neoplasms. Encouragingly, the few available examples support important roles for JHDMs in pediatric neoplasia, as well as potential roles for JHDM pharmacologic inhibition in disease management. Further investigations of JHDMs in cancer and other types of neoplasia of childhood can be expected to both enlighten disease biology and inform new approaches to improve disease outcomes.

KEYWORDS:

• Jumonji
• demethylase
• epigenetics
• cancer
• neoplasia
• pediatric

Article highlights

• Epigenetic mechanisms of gene regulatory control play fundamental roles in developmental morphogenesis, and, as more recently appreciated, are heavily implicated in the onset and progression of neoplastic disease, including cancer. Many epigenetic mechanisms are therapeutically targetable. The Jumonji-domain histone demethylase (JHDM) family exemplifies these traits.

• The JHDM family consists of roughly 20 genes/proteins that remove methyl groups from modified histones, using the Jumonji-C (JmjC) domain, and Fe²⁺ and α-ketoglutarate as cofactors. Histone mark specificity varies among the different subfamily members and helps determine effects on gene expression. All JHDMs are multi-domain proteins, but, at this time, the biological functions of additional domains are much less well understood than those of the JmjC demethylase domain.

• The biology of most JHDMs has been investigated in adult cancers. Here, different JHDMs have been found to exert context-dependent effects ranging from predominantly disease-promoting to mainly disease-suppressive. Encouragingly, from a pharmacologic targeting perspective, several JHDMs appear to behave predominantly to exclusively as disease-promoting factors.

• At this time, comparatively few studies have addressed JHDM biology in cancer and other neoplastic diseases of childhood, especially solid (non-hematopoietic) neoplasms. However, the few available examples support important roles for JHDMs in pediatric neoplasia, as well as potential roles for JHDM pharmacologic inhibition in disease management.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Support for this work was provided by the National Cancer Institute (T32-CA190216 to TSM; F31-CA203053 to MS; R01-CA183874 to PJ).