NKX3.1 Localization to Mitochondria Suppresses Prostate Cancer Initiation.

Papachristodoulou, Alexandros; Rodríguez-Calero, Antonio; Panja, Sukanya; Margolskee, Elizabeth; Virk, Renu K; Milner, Teresa A; Martina, Luis Pina; Kim, Jaime Y; Di Bernardo, Matteo; Williams, Alanna B; Maliza, Elvis A; Caputo, Joseph M; Haas, Christopher; Wang, Vinson; De Castro, Guarionex Joel; Wenske, Sven; Hibshoosh, Hanina; McKiernan, James M; Shen, Michael M; Rubin, Mark A; ... (2021). NKX3.1 Localization to Mitochondria Suppresses Prostate Cancer Initiation. Cancer discovery, 11(9), pp. 2316-2333. American Association for Cancer Research 10.1158/2159-8290.CD-20-1765

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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.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie 04 Faculty of Medicine > Service Sector > Institute of Pathology 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
UniBE Contributor:	Rodríguez Calero, José Antonio, Rubin, Mark Andrew
Subjects:	500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health
ISSN:	2159-8290
Publisher:	American Association for Cancer Research
Language:	English
Submitter:	Marla Rittiner
Date Deposited:	24 Jan 2022 13:52
Last Modified:	05 Dec 2022 16:00
Publisher DOI:	10.1158/2159-8290.CD-20-1765
PubMed ID:	33893149
URI:	https://boris.unibe.ch/id/eprint/163465