NKX3.1 Localization to Mitochondria Suppresses Prostate Cancer Initiation

Abstract

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

Extensive germline-somatic interplay drives prostate cancer through HNF1B co-option of TMPRSS2-ERG

“…1a), including many with poorly characterized causal roles (Fig. 1b), except for HOXB13, RFX6, and NKX3-1 that have been shown to be causally linked to PCa susceptibility and tumorigenesis [47][48][49][50] . Remarkably, the 17q12/HNF1B locus with several independent SNPs has been reproducibly found in association with PCa susceptibility (Fig.…”

Folic Acid–Modified miR-491-5p–Loaded ZIF-8 Nanoparticles Inhibit Castration-Resistant Prostate Cancer by Regulating the Expression of EPHX1

“…Many studies have shown that differentially expressed proteins in PCa affect its development and that most of these proteins are regulated at the transcriptional level and in turn regulate related signaling pathways (Nam et al, 2021;Papachristodoulou et al, 2021; (C) Cell immunofluorescence assay showed that the folate receptor (FAR) was overexpressed in C4-2 cells. (D) Laser scanning confocal microscopy was used to verify the cell internalization of FA@ZIF-8 and ZIF-8.…”

“…Many studies have shown that differentially expressed proteins in PCa affect its development and that most of these proteins are regulated at the transcriptional level and in turn regulate related signaling pathways ( Nam et al, 2021 ; Papachristodoulou et al, 2021 ; Shi et al, 2021 ; Yang et al, 2021 ). Studies have proven that miRNAs and their regulatory genes play important roles in the development of PCa ( Wei et al, 2007 ; Deng et al, 2013 ).…”

Gene of the month: NKX3.1

“…Free radicals resulting from hydrogen peroxide or paraquat treatment resulted in translocation of NKX3.1 to the mitochondria to upregulate genes in the electron transport chain. This challenged the idea that NKX3.1 is exclusively nuclear in location and highlighted a role separate from androgen signalling 13 . A separate study suggested that NKX3.1 may act as a paracrine transcription factor to regulate gene expression programs of neighbouring cells.…”