Abstract 1498: Melanoma antigen gene A6 and androgen receptor interaction in bladder cancer

Abstract

Abstract The Melanoma Antigen Gene (MAGE) protein family is a large and highly conserved group of proteins that share a common MAGE homology domain. Interestingly, several MAGE proteins are limited in expression to reproductive tissues but are aberrantly expressed in various types of human malignancies. We have recently demonstrated overexpression of MAGE family member A6 in advance-stage bladder cancer (Cancers 13:23, 5931, 2021). However, the mechanisms involved in MAGE gene overexpression and its coregulators are currently unknown. One hypothesis is that MAGEA6 and androgen receptor (AR) signaling is involved in the etiology of bladder cancer progression. In the present study, we determined the functional relationship between MAGEA6 and AR in bladder cancer. Treatment with DHT, an AR agonist, increased AR and MAGEA6 expression in UMUC3 and J82 bladder cancer cells at the protein and transcript level. On the contrary, exposure of cells to enzalutamide, an antiandrogen, resulted in simultaneous reduction of AR and MAGEA6 more prominently in UMUC3 cells, compared to J82 harboring low MAGEA6 transcript. Dual-sgRNA CRISPR/Cas9 knockout of MAGEA6 in UMUC3 and J82 cells resulted in inhibition of cell proliferation, reduced survival, and migration potential in both cell lines. An induction of S-phase and G0/G1 phase cell cycle arrest was noted in UMUC3 and J82 cells. In silico analysis showed Arg20 and Cys557 amino acid residue of AR interacts with Asp236 and Gln106 amino acid residue of MAGEA6 through hydrogen bonds. Further confirmation of physical interaction between AR and MAGEA6, performed by immunoprecipitation of AR and probed for MAGEA6 and vice versa established interaction of AR-MAGEA6 with each other which was further confirmed by mass spectrometry analysis. In conclusion, these findings confirm the oncogenic role of MAGEA6 and its physical interaction with AR may be involved in bladder cancer progression. Citation Format: Prem Prakash Kushwaha, Shiv Verma, Sanjay Gupta. Melanoma antigen gene A6 and androgen receptor interaction in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1498.