Before discovery of their histone demethylase function the J

Before discovery of their histone demethylase function, the JARID1 isoforms were identified across diverse fields including stem cell biology and congenital disease, as detailed in Box 2. Their observed roles in cancer progression and therapy resistance have led to ongoing pursuit of inhibitors tailored to unique features of the JARID1 family’s catalytic domain. Despite this effort, use of inhibitors is impaired by limited understanding of the biologic contributions of JARID1 demethylases to disease states. Here we review known functions of JARID1 family members in cancer and highlight the potential of targeting aspects of chromatin regulation mediated by these demethylases to improve cancer therapy.
JARID1 Proteins in Cancer
JARID1-Mediated Transcriptional Regulation
JARID1 Contribution to Cancer Progression
Targeting JARID1 Function Small-molecule inhibitors of JARID1 proteins are actively being pursued as anticancer therapeutics [72] and for treatment of certain nonmalignant diseases [73]. Early inhibition strategies used Fe2+ chelation or competitive 2-oxoglutarate analogs to impede the catalytic mechanism that JARID1 proteins share with many histone demethylases. The development of inhibitors with improved specificity has been hindered by the close structural homology and hybrid features of the JARID1 catalytic core with the KDM4 and KDM6 families [74]. This limitation explains the lack of specificity of early inhibitors such as 2,4-PDCA [75], PBIT [76], and hydroxamate compounds [77]. A nonselective inhibitory mechanism based on the ability of disulfiram to inhibit the binding of JARID1A’s PHD3 to H3K4me3 has also been described and used to inhibit the growth of AMLs driven by a NUP98–JARID1A fusion gene [78]. Recent structural analyses identifying amino Beauvericin side chains and conformational plasticity unique to the JARID1 active sites have facilitated improvements in the potency and selectivity of inhibitors 79, 80. Presently the most notable result is CPI-455, a prototype tool compound with 200-fold selectivity for JARID1 over KDM4 demethylases and at least 500-fold selectivity over other KDM families [81]. 1,7-Naphthyridones are a second recent example of a small-molecule class with potential JARID1 family specificity [82]. Two other lead compounds have been described with selectivity for the JARID1A isoform 83, 84. In general, the biologic effects of these JARID1 inhibitors in vitro appear fairly modest. However, their effects in tumor and host, either as a single agent or in combinatorial use, are largely unknown and difficult to anticipate given the diverse, context-specific roles of these large, multifunction proteins. The contextual basis of these effects may be determined in large part by associations with larger chromatin regulatory complexes, detailed in Box 3.
Concluding Remarks Interest in the role of JARID1 proteins in development and cancer has increased steadily since 2007, when they were recognized as H3K4 demethylases 3, 85, 86, 87, 88, 89, 90. This interest is sustained partly by the observation that upregulation of these chromatin regulators can mediate a cancer cell state characterized by stem cell-like features, aggressive invasion and metastasis, and therapy resistance. The mechanisms by which JARID1 proteins contribute to cancer progression overlap with those in development but are also likely to include gene regulatory actions unique to malignancy. To date, work to define these mechanisms in cancer has mainly considered demethylase-dependent repression of specific promoters and not the broader range of potential gene regulatory effects, including demethylase independent ones. Actions of JARID1 proteins in cancer that are potentially targetable by demethylase inhibition are highlighted in Figure 2. Which effects are demethylase dependent needs to be determined to clarify the features of cancers that are targetable via JARID1 enzymatic activity (see Outstanding Questions) and this effort is made timely by the recent emergence of potent tool drugs with selectivity for the JARID1 family. In addition, the diverse binding partners that dictate the gene specificity of JARID1 proteins underscore their cell-context dependence as drug targets and highlight the need to identify molecular subgroups of tumors where targeting them has relevance. Despite these caveats, targeting the JARID1 family and other histone modifiers holds promise in combination therapies designed to address the epigenetic plasticity that allows malignant cells to escape current cancer drugs. Clarifying the interface of the JARID1 family with the DNA damage response may guide the application of these inhibitors, with numerous cytotoxic or targeted drugs impacting this process. Similarly, combining JARID1 inhibitors with select targeted agents that inhibit oncogenic signaling pathways may address the epigenetic plasticity that can prevent such modern drugs from achieving durable cancer control.