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NKX3.1 localization to mitochondria suppresses prostate cancer initiation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE115338 | GEO | 2021/04/13

REPOSITORIES: GEO

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NKX3.1 Localization to Mitochondria Suppresses Prostate Cancer Initiation.

Project description: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.

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NKX3.1 localization to mitochondria suppresses prostate cancer initiation (Mouse 4M Prostate RNASeq)

Project description:The NKX3.1 homeobox gene functions in mitochondria to regulate oxidative stress To investigate the role of NKX3.1 in regulation of oxidative stress, we employed transcriptome analysis of mouse prostate ( from 4 month old Nkx3.1+/+ and Nkx3.1-/- mice treated with paraquat), and human prostate cells ( RWPE1 cells engineered with empty vector (altered pTRIPZ), NKX3.1 wild type over-expression, and NKX3.1 (R52C) over-expression treated with paraquat). Mouse tissue or human cells were snap frozen for subsequent molecular analysis.

2021-04-13 | GSE115337 | GEO

NKX3.1 localization to mitochondria suppresses prostate cancer initiation

Project description:NKX3.1 localization to mitochondria suppresses prostate cancer initiation

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NKX3.1 localization to mitochondria suppresses prostate cancer initiation (Human RWPE1 RNASeq)

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NKX3.1 localization to mitochondria suppresses prostate cancer initiation (Mouse 4M Prostate RNASeq)

Project description:NKX3.1 localization to mitochondria suppresses prostate cancer initiation (Mouse 4M Prostate RNASeq)

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NKX3.1 localization to mitochondria suppresses prostate cancer initiation (Human RWPE1 RNASeq)

Project description:NKX3.1 localization to mitochondria suppresses prostate cancer initiation (Human RWPE1 RNASeq)

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Cooperation of loss of NKX3.1 and inflammation in prostate cancer initiation.

Project description:Although it is known that inflammation plays a critical role in prostate tumorigenesis, the underlying processes are not well understood. Based on analysis of genetically engineered mouse models combined with correlative analysis of expression profiling data from human prostate tumors, we demonstrate a reciprocal relationship between inflammation and the status of the NKX3.1 homeobox gene associated with prostate cancer initiation. We find that cancer initiation in aged Nkx3.1 mutant mice correlates with enrichment of specific immune populations and increased expression of immunoregulatory genes. Furthermore, expression of these immunoregulatory genes is similarly increased in human prostate tumors having low levels of NKX3.1 expression. We further show that induction of prostatitis in Nkx3.1 mutant mice accelerates prostate cancer initiation, which is coincident with aberrant cellular plasticity and differentiation. Correspondingly, human prostate tumors having low levels of NKX3.1 have de-regulated expression of genes associated with these cellular processes. We propose that loss of function of NKX3.1 accelerates inflammation-driven prostate cancer initiation potentially via aberrant cellular plasticity and impairment of cellular differentiation.This article has an associated First Person interview with the first author of the paper.

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