NKX3.1 Localization to Mitochondria Suppresses Prostate Cancer Initiation.
Alexandros PapachristodoulouJosé Antonio Rodriguez-CaleroSukanya PanjaElizabeth MargolskeeRenu K VirkTeresa A MilnerLuis Pina MartinaJaime Y KimMatteo Di BernardoAlanna B WilliamsElvis A MalizaJoseph M CaputoChristopher HaasVinson WangGuarionex Joel De CastroSven WenskeHanina HibshooshJames M McKiernanMichael M ShenMark A RubinAntonina MitrofanovaAditya DuttaCory Abate-ShenPublished in: Cancer discovery (2021)
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.
Keyphrases
- prostate cancer
- oxidative stress
- radical prostatectomy
- poor prognosis
- dna damage
- risk assessment
- endothelial cells
- ischemia reperfusion injury
- cell death
- diabetic rats
- binding protein
- induced apoptosis
- papillary thyroid
- reactive oxygen species
- mouse model
- dna repair
- squamous cell carcinoma
- long non coding rna
- emergency department
- transcription factor
- heat shock
- gene expression
- machine learning
- heat shock protein
- lymph node metastasis
- pluripotent stem cells
- small molecule
- amino acid
- childhood cancer
- climate change
- heavy metals
- squamous cell
- heat stress
- bioinformatics analysis