The androgen receptor (AR) plays an important role in normal development of the prostate gland, in prostate carcinogenesis, and in the progression of prostate cancer to advanced metastatic disease. Traditional thinking is that AR localizes exclusively to the nucleus and that nuclear AR regulates genes that are essential to prostate cancer development. This is true. However, we demonstrate a previously unrecognized function of AR in mitochondria. We have discovered that AR 1) directly localizes into the mitochondria and 2) indirectly transcriptionally regulates nuclear genes whose products localize into mitochondria and perform mitochondrial functions. Our studies reveal that i) AR localizes into mitochondria in primary prostate tissues and cell lines, ii) AR is imported into isolated mitochondria, and iii) AR contains a mitochondrial localization signal (MLS) capable of targeting foreign proteins, such as green fluorescent protein, into mitochondria. Indirectly, AR controls expression of a variety of nuclear DNA (nDNA)-encoded mitochondrial oxidative phosphorylation (mtOXPHOS) subunits, including NDUFB8 (Complex I), SDHB (Complex II), UQCRC2 (Complex III), COXII subunit (Complex IV), and ATP5A (Complex V). AR also down-regulates the TFAM, GFM1, and GFM2 genes, which control mitochondrial DNA (mtDNA) content. Consistent with this, the mtDNA content and the expression of mtDNA-encoded COX II protein is significantly reduced in PC3-AR prostate cells expressing AR. Notably, we demonstrate that the mtDNA content in prostate tumors of African-Americans (AA) is >6 times less than in tumors of Caucasian-Americans (CA). mtDNA content was also lower in normal prostates of AA than CA. To identify the underlying mitochondrial basis of prostate cancer diversity, we conducted comprehensive, race-based bioinformatics analyses of variants in more than 6000 AA and 33,000 CA and discovered, in the AR gene of AA, missense variants located in two domains: the N-terminal domain containing the MLS and the DNA-binding domain. Of note, missense mutations in CA were found only in the hinge domain containing the nuclear localization signal (NLS) of AR. Expression of AR variant S598G in PC3 cells reduced more than the wild type the expression of TFAM, which controls mtDNA content. We hypothesize that AR missense variants/mutants present, solely in AA, contribute to the gain or loss of mitochondrial function and thereby to prostate cancer diversity in AA.
AIM 1 : Determine the prognostic significance of AR missense variants/mutants and mtDNA content on prostate cancer metastasis and reoccurrence in AA and CA.
AIM 2 : Evaluate the significance of mitochondrial AR missense variants/mutants as direct regulators of mitochondrial functions that affect composition, organization, stability, and activity of mtOXPHOS super-complexes and apoptosis.
AIM 3 : Evaluate the significance of nuclear AR missense variants/mutants as indirect regulators of mitochondrial function.
AIM 4 : Use mouse xenograft model to establish the significance of mitochondrial and nuclear AA- and CA-specific AR missense variants/mutants on prostate tumorigenesis and metastasis.
| Singh, Bhupendra; Schoeb, Trenton R; Bajpai, Prachi et al. (2018) Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function. Cell Death Dis 9:735 |
| Koo, Dal-Hoe; Singh, Bhupendra; Jiang, Jiming et al. (2018) Single molecule mtDNA fiber FISH for analyzing numtogenesis. Anal Biochem 552:45-49 |
| Choudhury, Aaheli Roy; Singh, Keshav K (2017) Mitochondrial determinants of cancer health disparities. Semin Cancer Biol 47:125-146 |
| Singh, Keshav K; Choudhury, Aaheli Roy; Tiwari, Hemant K (2017) Numtogenesis as a mechanism for development of cancer. Semin Cancer Biol 47:101-109 |
| Singh, Bhupendra; Modica-Napolitano, Josephine S; Singh, Keshav K (2017) Defining the momiome: Promiscuous information transfer by mobile mitochondria and the mitochondrial genome. Semin Cancer Biol 47:1-17 |
| Carden, Trevor; Singh, Bhupendra; Mooga, Ved et al. (2017) Epigenetic modification of miR-663 controls mitochondria-to-nucleus retrograde signaling and tumor progression. J Biol Chem 292:20694-20706 |
