From Germline Antigen to Tumor Advantage: MAGEA6 Reprograms Autophagy via AMPK to Sustain Chemoresistance

The melanoma-associated antigen family A (MAGEA) proteins are a group of cancer/testis antigens (CTAs) present only in male germ cells and can be re-expressed in cancer cells by promoter hypomethylation due to epigenetic regulation. Melanoma-associated antigen A6 (MAGEA6) is a proto-oncogene well known to have oncogenic activity and regulates the tumor progression and chemotherapy resistance. There is a strong evidenec in triple negative breast cancer (TNBC), that by targetting autophagy the sensitivity to chemotherapy increases and due to its high specificity to cancer cells it makes an excellent immunotherapeutic target. Even though there are evidences that there is an increased expression of MAGEA in treatment resistant tumors the functional effects of MAGEA6 is not fully understood.

The Cancer Genome Atlas (TCGA) dataset, the clinical samples and the TNBC cell lines on analysis showed that MAGEA6 was significantly expressed in breast cancer. MAGEA6 was also found to be up-regulated in doxorubicin (DOX)-resistant TNBC cells. Upon transfecting TNBC cells with sh-MAGEA6 vector, MAGEA6 was successfully knocked down and knockdown of MAGEA6 also increased autophagosomes . MTT assay showed MAGEA6 improved the chemo-sensitivity of TNBC cells to DOX.

According to Gene Ontology (GO)—the biological process, MAGEA6 t is involved in the negative regulation of autophagy. The in vitro, ubiquitination assay displayed that silencing MAGEA6 decreased the AMPKα1 ubiquitination in TNBC cells. AMPKα1 is a catalytic subunit of AMPK which can drive autophagy upon activation. Overexpression of MAGEA6 in cell lines accelerated the ubiquitination of AMPKα1. AMPKα1 was also found to be co-immunoprecipitated along with MAGEA6 upon overexpression. In vivo analysis of MAGEA6 on DOX sensitivity using a xenograft tumor model with knocked down MAGEA6 showed decreased ki67 expression, but increase of Cleaved caspase3.

This suggests a potential mechanism of MAGEA6 mediated degradation of AMPKα1 by ubiquitination influences autophagy and enhances chemo resistance. Further research on MAGEA and  AMPK would help in understanding of the biology to develop innovative targeted therapy potential oncogenic drivers.

REFERENCE:

Zhu, H., Jiang, Cw., Zhang, Wl. et al. Targeting oncogenic MAGEA6 sensitizes triple negative breast cancer to doxorubicin through its autophagy and ferroptosis by stabling AMPKα1. Cell Death Discov. 10, 430 (2024). https://doi.org/10.1038/s41420-024-02196-9

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