From histones to ribosomes: a chromatin regulator tangoes with translation

Abstract

Histone lysine methylation is a critical regulator of chromatin-templated processes such as gene transcription and DNA repair, and is dynamically controlled by enzymes that write and erase this posttranslational modification. Although histone methylation has been well studied, the functions of nonhistone lysine methylation and its regulatory enzymes, particularly outside the nucleus, are poorly defined. In this issue of Cancer Discovery, Van Rechem and colleagues shed light on a new role for the lysine demethylase KDM4A as a regulator of protein translation and identify a single-nucleotide polymorphism in the KDM4A gene as a candidate biomarker for mTOR inhibitor therapy.

Figure 1. Compartmentalized cellular functions of KDM4A

Cartoon depicting the known nuclear and newly uncovered cytoplasmic roles of KDM4A. Shown are receptor tyrosine kinase (RTK) and glucose signaling axes that elicit control on mTORC1, a key regulator of protein synthesis. Whetstine and colleagues show that KDM4A regulates protein synthesis in the cytoplasm through its association with translation initiation factors. They further show that an identified SNP-482 in KDM4A promotes its turnover by targeting it to the SCF ubiquitin ligase complex. Loss of KDM4A or inhibition of catalytic activity with a small molecule (JIB-04) enhances therapeutic effects of rapamycin and other mTORC1 inhibitors.