Open AccessNKX3.1 Localization to Mitochondria Suppresses Prostate Cancer Initiation
Author(s) -
Alexandros Papachristodoulou,
Antonio Rodriguez-Calero,
Sukanya Panja,
Elizabeth Margolskee,
Renu K. Virk,
Teresa A. Milner,
Luis Pina Martina,
Jaime Y. Kim,
Matteo Di Bernardo,
Alanna B. Williams,
Elvis A. Maliza,
Joseph M. Caputo,
Christopher Haas,
Vinson Wang,
Guarionex Joel De Castro,
Sven Wenske,
Hanina Hibshoosh,
James M. McKiernan,
Michael M. Shen,
Mark A. Rubin,
Antonina Mitrofanova,
Amitabh Dutta,
Cory AbateShen
Publication year - 2021
Publication title -
cancer discovery
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.795
H-Index - 163
eISSN - 2159-8290
pISSN - 2159-8274
DOI - 10.1158/2159-8290.cd-20-1765
Subject(s) - prostate cancer , mitochondrion , oxidative stress , biology , cancer research , cancer , dnaja3 , oxidative phosphorylation , cancer cell , chaperone (clinical) , mitochondrial dna , bioinformatics , microbiology and biotechnology , gene , medicine , genetics , mitochondrial fusion , endocrinology , biochemistry , pathology
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 .