The Cancer/Testis Antigen Gene VCX2 Is Rarely Expressed in Malignancies but Can Be Epigenetically Activated Using DNA Methyltransferase and Histone Deacetylase Inhibitors

Abstract

Identification of novel tumor-specific targets is important for the future development of immunotherapeutic strategies using genetically engineered T cells or vaccines. In this study, we characterized the expression of VCX2, a member of the VCX/Y cancer/testis antigen family, in a large panel of normal tissues and tumors from multiple cancer types using immunohistochemical staining and RNA expression data. In normal tissues, VCX2 was detected in the germ cells of the testis at all stages of maturation but not in any somatic tissues. Among malignancies, VCX2 was only found in tumors of a small subset of melanoma patients and thus rarely expressed compared to other cancer/testis antigens such as GAGE and MAGE-A. The expression of VCX2 correlated with that of other VCX/Y genes. Importantly, we found that expression of VCX2 was inversely correlated with promoter methylation and could be activated by treatment with a DNA methyltransferase inhibitor in multiple breast cancer and melanoma cell lines and a breast cancer patient-derived xenograft. The effect could be further potentiated by combining the DNA methyltransferase inhibitor with a histone deacetylase inhibitor. Our results show that the expression of VCX2 can be epigenetically induced in cancer cells and therefore could be an attractive target for immunotherapy of cancer.

Higher Expression Levels of SSX1 and SSX2 in Patients with Colon Cancer: Regulated In Vitro by the Inhibition of Methylation and Histone Deacetylation

“…The expressions of the SSX1 and SSX2 genes were found in the advanced grades of CC tissue samples, according to the clinical data of the study participants (grades II and III). Consistent with previous reports on SSX family expression in a range of human cancers (9,17,18), SSX gene expression has been correlated with more advanced stages of disease [23][24][25]. Previous studies have identified the same findings for SSX genes in patients with CC [17].…”

“…DNA methylation and histone acetylation are epigenetic processes that have been shown to influence the expressions of various CT genes [ 7 , 9 , 11 , 18 ]. With regard to DNA methylation, DNA methyltransferase enzymes (DNMTs) control the expressions of diverse CT genes by adding large amounts of a methyl group (CH₃) to their promoter regions, silencing them.…”

“…With regard to DNA methylation, DNA methyltransferase enzymes (DNMTs) control the expressions of diverse CT genes by adding large amounts of a methyl group (CH₃) to their promoter regions, silencing them. This process is called DNA hypermethylation [ 11 , 18 ]. By contrast, the treatment of cell lines with DNA methyltransferase inhibitor (DNMTi) drugs, such as 5-aza-2′-deoxycytidine (5-aza-CdR), allows for the experimental DNA hypomethylation of several CT genes, which removes the CH₃ groups and promotes increased CT gene expression levels [ 7 , 9 ].…”

In Vivo Modeling of Tumor Heterogeneity for Immuno‐Oncology Studies: Failures, Improvements, and Hopes

“…Additionally, hypomethylating agents upregulate the antigen presentation machinery and cancer testis antigens in solid and hematological cancer cells (Siebenkäs et al., 2017; Srivastava et al., 2016). Importantly, cancer testis antigens are highly immunogenic tumor‐specific antigens that are expressed aberrantly in several cancer types and are the focus of new immunotherapy targets (Jakobsen & Gjerstorff, 2020; Jakobsen et al., 2021).…”

Melanoma Antigen Family A (MAGE A) as Promising Biomarkers and Therapeutic Targets in Bladder Cancer

“…The mechanisms that control the unusual MAGEAs are still under exploration. MAGEAs are infrequently express sues; however, epigenetic changes including DNA hypermethylation o tides in promoters and posttranslational modifications of the histone pro scription factors from binding, and thus represses the expression of MA Further studies have shown that DNA methyltransferases (DNMTs) inh aza-2-deoxycytidine, result in the increased expression of MAGEA1 in s cells [35]. This effect can be additionally reinforced using histone deac [35,36].…”