Spatiofunctional Dynamics of NKX3.1 to Safeguard the Prostate from Cancer
| Autor: | Esther Baena, Andrew J. Finch |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Mitochondrion urologic and male genital diseases medicine.disease_cause Article Transcription (biology) Prostate medicine Humans HSPA9 Homeodomain Proteins chemistry.chemical_classification Reactive oxygen species urogenital system Prostatic Neoplasms Cancer medicine.disease Electron transport chain Cell biology medicine.anatomical_structure Oncology chemistry Reactive Oxygen Species Oxidative stress Transcription Factors |
| Zdroj: | Cancer Discov |
| ISSN: | 2159-8290 2159-8274 |
| DOI: | 10.1158/2159-8290.cd-21-0861 |
| Popis: | Mitochondria provide the front-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. STATEMENT OF SIGNIFICANCE: Our findings uncover a non-nuclear function for NKX3.1 that is a key mechanism for suppression of prostate cancer. Analyses of the expression levels and sub-cellular 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. |
| Databáze: | OpenAIRE |
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