Epigenetic Upregulation of MAGE-A Isoforms Promotes Breast Cancer Cell Aggressiveness

Abstract

After decades-long efforts to diagnose and treat breast cancer, the management strategy that has proved most successful to date is molecular-subtype-specific inhibition of the hormone receptors and HER2 that are expressed by individual cancers. Melanoma-associated antigen (MAGE) proteins comprise >40 highly conserved members that contain the MAGE homology domain. They are often overexpressed in multiple cancers and contribute to cancer progression and metastasis. However, it remains unclear whether the biological activity arising from MAGE gene expression is associated with breast cancer subtypes. In this study, we analyzed the RNA-sequencing (RNA-seq) data of 70 breast cancer cell lines and found that MAGEA12 and MAGEA3 were highly expressed in a subset of these lines. Significantly, MAGEA12 and MAGEA3 expression levels were independent of hormone receptor expression levels but were closely associated with markers of active histone modifications. This indicates that overexpression of these genes is attributable to epigenetic deregulation. RNA-seq of MAGEA12-depleted cells was then used to identify 382 candidate targets of MAGEA12 that were downregulated by MAGEA12 depletion. Furthermore, our gain-of-function experiments showed that MAGEA12 overexpression promoted aggressive behaviors of malignant breast cancer cells, including enhancing their cell migration and invasion. These changes were associated with increased epigenetic deregulation of the MAGEA12 signature genes. Thus, MAGEA12 may play an important role in breast cancer malignancy. Taken together, our findings suggest that MAGEA12 could be a promising therapeutic target in breast cancer, and its overexpression and epigenetic changes could serve as subtype classification biomarkers.

Identification of Cancer/Testis Antigens Related to Gastric Cancer Prognosis Based on Co-Expression Network and Integrated Transcriptome Analyses

“…investigated the MAGEA12 in breast cancer and found that it promotes malignancy. [ 30 ] MAGEA12 expression is contributed to histone modifier proteins. This protein up-regulation attributes to epigenetic modifications.…”

“…This protein up-regulation attributes to epigenetic modifications. [ 30 ] The functional enrichment analysis of differentially-expressed CTA genes showed that MAGEA3, 6, 12, and CSAG3 are involved in binding proteins. Maxfield et al .…”

“…Studies reveal that MAGEA3 confers proliferation and chemoresistance. [ 30 33 34 ] Wang et al . investigated Sitagliptin in gastric cancer.…”

A Death-Related Gene Signature for Prognosis with Osteosarcoma

“…MAGEA12 has been shown to act as a prognostic-related gene in gastric cancer [20]. In addition, overexpression of MAGEA12 is involved in the pathogenesis of human cutaneous squamous cell carcinoma and can also promote invasion of breast cancer cells [21,22]. The study by Chuzhao Lin et al reported that cancer/testis antigen CSAGE was concurrently expressed with MAGE in chondrosarcoma [23].…”

Evaluation of the TCR Repertoire as a Predictive and Prognostic Biomarker in Cancer: Diversity or Clonality?

“…Cancer germline antigens derive from proteins that are naturally expressed during foetal development and in certain types of tumours but are usually unexpressed in adult normal tissues. The most investigated cancer germline antigens are NY-ESO-1 and MAGE-A antigens, first reported in patients with synovial cell sarcoma or melanoma [ 36 , 37 , 38 , 39 , 40 , 41 ], but also described in several other types of tumours [ 38 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. Differentiation antigens are specific proteins from tissue or cells, both healthy and affected, where the tumour is occurring, but that are not expressed in other tissues, as CD19 in most of B cell lymphomas [ 35 , 54 ] or gp100 and MART-1 in melanoma [ 55 , 56 ]).…”