Clues to cancer from an identity change: The prostate and seminal vesicle have closely related developmental histories and both are regulated by the same androgenic hormones. A better understanding of the molecular mechanisms controlling the development of the two tissues could help solve why cancer arises frequently in the prostate but only rarely in seminal vesicles. Working with cell and mouse models, Dutta et al. show that forced expression of a single gene, the homeobox gene NKX3.1 , causes seminal vesicle epithelium to differentiate into prostate. NKX3.1 regulates the expression of a gene program associated with prostate differentiation by interacting with the G9a histone methyltransferase. Disruption of this regulatory network probably contributes to prostate cancer development. Science , this issue p. 1576

Mitochondria provide the first line of defense against the tumor-promoting effects of oxidative stress. Here we show that the prostate-specific homeoprotein NKX3.1 suppresses prostate cancer initiation by protecting mitochondria from oxidative stress. Integrating analyses of genetically engineered mouse models, human prostate cancer cells, and human prostate cancer organotypic cultures, we find that, in response to oxidative stress, NKX3.1 is imported to mitochondria via the chaperone protein HSPA9, where it regulates transcription of mitochondrial-encoded electron transport chain (ETC) genes, thereby restoring oxidative phosphorylation and preventing cancer initiation. Germline polymorphisms of NKX3.1 associated with increased cancer risk fail to protect from oxidative stress or suppress tumorigenicity. Low expression levels of NKX3.1 combined with low expression of mitochondrial ETC genes are associated with adverse clinical outcome, whereas high levels of mitochondrial NKX3.1 protein are associated with favorable outcome. This work reveals an extranuclear role for NKX3.1 in suppression of prostate cancer by protecting mitochondrial function. Significance: Our findings uncover a nonnuclear function for NKX3.1 that is a key mechanism for suppression of prostate cancer. Analyses of the expression levels and subcellular localization of NKX3.1 in patients at risk of cancer progression may improve risk assessment in a precision prevention paradigm, particularly for men undergoing active surveillance. See related commentary by Finch and Baena, p. 2132. This article is highlighted in the In This Issue feature, p. 2113

Aims: Plants employ both basal and resistance gene ( R gene)-mediated defenses in response to pathogens. Reactive oxygen species (ROS) are widely reported to play a central role in both basal and R gene-mediated defense; however, the nature of ROS has been less well established for basal defense. In addition, spatial distribution of redox moieties and mechanisms of plant responses during basal defense are poorly understood. We investigated redox signaling in Arabidopsis thaliana in response to virulent bacterial pathogen, focusing on the role of the mitochondria in balancing energy demands against generation of physiologically relevant ROS. Results: Positional cloning of an Arabidopsis lesion mimic mutant identified a polyprenyl transferase involved in the biosynthesis of Coenzyme Q ₁₀ (CoQ), which leads to novel insights into physiological ROS levels and their role in basal resistance. Gain- and loss-of-function studies identified Coenzyme Q ₁₀ redox state to be a key determinant of ROS levels. These Coenzyme Q ₁₀ redox state-mediated ROS levels had a direct bearing on both response against pathogen and ability to thrive in high oxidative stress environments. Innovation: We demonstrate that Coenzyme Q ₁₀ redox state generates an ROS threshold for a successful basal resistance response. Perturbation of the Coenzyme Q ₁₀ redox state has the potential to disrupt plant defense responses against bacterial pathogens. Conclusions: Coenzyme Q ₁₀ redox state is a key regulator of Arabidopsis basal resistance against bacterial pathogens. Antioxid. Redox Signal . 22, 785–796.