Increased Expression of Androgen Receptor Coregulator MAGE-11 in Prostate Cancer by DNA Hypomethylation and Cyclic AMP

Abstract

Melanoma antigen gene protein-A11 (MAGE-11) of the MAGE family of cancer germ-line antigens increases androgen receptor (AR) transcriptional activity through its interaction with the AR NH 2 -terminal FXXLF motif. The present study investigated the regulatory mechanisms that control MAGE-11 expression during androgen deprivation therapy and prostate cancer progression. Studies include the CWR22 xenograft model of human prostate cancer, clinical specimens of benign and malignant prostate, and prostate cancer cell lines. MAGE-11 mRNA levels increased 100-to 1,500-fold during androgen deprivation therapy and prostate cancer progression, with highest levels in the castration-recurrent CWR22 xenograft and clinical specimens of castration-recurrent prostate cancer. Pyrosequencing of genomic DNA from prostate cancer specimens and cell lines indicated the increase in MAGE-11 resulted from DNA hypomethylation of a CpG island in the 5′ promoter of the MAGE-11 gene. Sodium bisulfite sequencing of genomic DNA from benign and malignant prostate tumors and prostate cancer cell lines revealed DNA hypomethylation at individual CpG sites at the transcription start site were most critical for MAGE-11 expression. Cyclic AMP (cAMP) also increased MAGE-11 expression and AR transcriptional activity in prostate cancer cell lines. However, cAMP did not alter DNA methylation of the promoter and its effects were inhibited by extensive DNA methylation in the MAGE-11 promoter region. Increased expression of the AR coregulator MAGE-11 through promoter DNA hypomethylation and cAMP provides a novel mechanism for increased AR signaling in castration-recurrent prostate cancer. (Mol Cancer Res 2009;7(4):523-35)

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

“…Induction of AIM in a previous study of 23 EOC cell lines included, in addition to previously reported DNA hypermethylated cancer testis antigens (MAGEA4, MAGEA9, NY-ESO-1) (James et al, 2013;Karpf et al, 2009;Karpf et al, 2004;Odunsi et al, 2014), interferon/viral defense, antigen processing and presentation, and host immune cell attraction genes ( Figure 1a). Direct Aza targeting of DNMTs for these changes is suggested by similar findings in DKO colon cancer cells genetically disrupted for two major DNMTs (DNMT1−/−, DNMT3B −/−) versus parental, wild type HCT116 cells (Figure 1a).…”

Transgelin induces apoptosis of human prostate LNCaP cells through its interaction with p53

“…The proper function of AR requires coregulators for its optimal signalling. Several AR coregulators, including the cAMP response element-binding protein-binding protein, steroid receptor coactivator 1, ARA54, ARA67/PAT1, ARA70, hRad9 and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) have been identified [3,[13][14][15][16][17][18]. ARA54 enhances AR transactivation in a ligand-dependent manner [17,19,20].…”

Post-translational Down-regulation of Melanoma Antigen-A11 (MAGE-A11) by Human p14-ARF Tumor Suppressor

“…Expression and RNA Analysis-Cell media contained penicillin, streptomycin, and 2 mM L-glutamine (Gibco, Life Technologies) as follows: human LAPC-4 cells, RPMI 1640 with 10% FBS and 1 nM R1881 synthetic androgen agonist; 22Rv1 cells, RPMI 1640 with 10% FBS; LNCaP cells, RPMI 1640 with 2% FBS; human HeLa cervical cancer cells, minimal essential medium with 10% FBS; CV1 and COS1 monkey kidney cells, DMEM with 10% bovine calf serum and 20 mM Hepes, pH 7.2; PC-3 and DU145 cells, DMEM with 10% FBS; CWR-R1, DMEM with additives (2).…”

“…Prostate cancer growth and progression depend on androgen receptor (AR) 2 transcriptional signaling, which is increased by melanoma antigen-A11 (MAGE-A11), an AR coregulator. MAGE-A11 is a cancer-testis antigen that resides predominantly in the nucleus at low levels in normal human reproductive tract tissues and at higher levels in castration-resistant prostate cancer (1)(2)(3)(4)(5)(6).…”

“…MAGE-A11 is a cancer-testis antigen that resides predominantly in the nucleus at low levels in normal human reproductive tract tissues and at higher levels in castration-resistant prostate cancer (1)(2)(3)(4)(5)(6). Although named initially for its identification in melanoma (7,8), MAGE-A11 is a coregulator of human AR and progesterone receptor-B (1,6,9).…”