Data from NKX3.1 Suppresses <i>TMPRSS2–ERG</i> Gene Rearrangement and Mediates Repair of Androgen Receptor–Induced DNA Damage

<div>Abstract<p><i>TMPRSS2</i> gene rearrangements occur at DNA breaks formed during androgen receptor–mediated transcription and activate expression of <i>ETS</i> transcription factors at the early stages of more than half of prostate cancers. NKX3.1, a prostate tumor suppressor that accelerates the DNA repair response, binds to androgen receptor at the <i>ERG</i> gene breakpoint and inhibits both the juxtaposition of the <i>TMPRSS2</i> and <i>ERG</i> gene loci and also their recombination. NKX3.1 acts by accelerating DNA repair after androgen-induced transcriptional activation. NKX3.1 influences the recruitment of proteins that promote homology-directed DNA repair. Loss of NKX3.1 favors recruitment to the <i>ERG</i> gene breakpoint of proteins that promote error-prone nonhomologous end-joining. Analysis of prostate cancer tissues showed that the presence of a <i>TMPRSS2–ERG</i> rearrangement was highly correlated with lower levels of NKX3.1 expression consistent with the role of NKX3.1 as a suppressor of the pathogenic gene rearrangement. <i>Cancer Res; 75(13); 2686–98. ©2015 AACR</i>.</p></div>