The ABL kinases, ABL1 and ABL2, promote tumor progression and metastasis in various solid tumors. Recent reports have shown that ABL kinases have increased expression and/or activity in solid tumors and that ABL inactivation impairs metastasis. The therapeutic effects of ABL inactivation are due in part to ABL-dependent regulation of diverse cellular processes related to the epithelial to mesenchymal transition and subsequent steps in the metastatic cascade. ABL kinases target multiple signaling pathways required for promoting one or more steps in the metastatic cascade. These findings highlight the potential utility of specific ABL kinase inhibitors as a novel treatment paradigm for patients with advanced metastatic disease.
Melanoma Antigen Genes (MAGEs) are a family of genes that have piqued the interest of scientists for their unique expression pattern. A subset of MAGEs (Type I) are expressed in spermatogonial cells and in no other somatic tissue, and then re-expressed in many cancers. Type I MAGEs are often referred to as cancer-testis antigens due to this expression pattern, while Type II MAGEs are more ubiquitous in expression. This study determines the cause and consequence of the aberrant expression of the MAGE-A subfamily of cancer-testis antigens. We have discovered that MAGE-A genes are regulated by DNA methylation, as revealed by treatment with 5-azacytidine, an inhibitor of DNA methyltransferases. Furthermore, bioinformatics analysis of existing methylome sequencing data also corroborates our findings. The consequence of expressing certain MAGE-A genes is an increase in cell proliferation and colony formation and resistance to chemo-therapeutic agent 5-fluorouracil and DNA damaging agent sodium arsenite. Taken together, these data indicate that DNA methylation plays a crucial role in regulating the expression of MAGE-A genes which then act as drivers of cell proliferation, anchorage-independent growth and chemo-resistance that is critical for cancer-cell survival.
Cancer‐testis antigens are a family of tumor specific proteins that are typically expressed in the male germline and then aberrantly expressed in many cancers. Melanoma Antigen Genes (MAGEs) are the largest family of cancer‐testis antigens and are divided into Type I and Type II MAGEs based on expression pattern. Type I MAGEs are true cancer testis antigens and their expression in tumors is often associated with poor patient prognosis. While cancers often express more than one Type I MAGE gene, this study focusses on MAGEB2, an exemplary member of the Type I gene family and therefor a bona fide cancer‐testis antigen. There is a significant gap in understanding the mechanisms that regulate expression of MAGEB2, and the role that aberrantly expressed MAGEB2 plays in cellular transformation. We hypothesized that epigenetic mechanisms such as DNA methylation, which regulates the expression of many germline genes also regulates MAGEB2 gene expression. Using bioinformatics and ChIP assays, we have determined the transcription factor networks that regulate MAGEB2 expression. In addition, we show that expressing MAGEB2 gene provides non‐transformed cells with a proliferative advantage by dampening TGFb signaling. Taken together our data indicate that cells use epigenetic memory to express MAGEB2 resulting in shift of the cells’ gene signature to a pro‐proliferative, anti‐apoptotic state that firmly places cells in the path to transformation.
Melanoma Antigen Genes (MAGEs) are defined as cancer‐testis antigens due to their unique expression pattern. There are two families of MAGEs, Type I and Type II. Type I MAGEs are expressed in the testis and in no other normal somatic tissue and then re‐expressed in many cancers. Type II MAGEs on the other hand, are ubiquitous in their expression, meaning they are expressed in various somatic tissues. MAGE‐B2 is a member of the Type I subfamily. Expression of MAGE‐B2 causes increases in cell proliferation by as yet unknown mechanisms. Furthermore, depletion of MAGE‐B2 from cancer cells decreases cell proliferation. Our data indicate that the levels of anti‐angiogenic protein Thrombospondin‐1 (TSP‐1) is lowered in MAGE‐B2 expressing cells. TSP‐1 is also known as a regulator of TGFb signaling, because it activates TGFb. We will first determine whether TGFb signaling effectors such as TGFb, TGFb‐receptor, or Smad proteins are altered in expression and/or activity because of aberrant levels of MAGE‐B2. Then, we will determine whether TSP‐1 and TGFb signaling pathway effectors are needed for MAGE‐B2 driven proliferation, using gain and loss of function assays. In summary, these studies will shed light on the mechanisms that MAGE‐B2 uses to drive cell proliferation. Support or Funding Information NSF HBCU UP: Research Initiation Award HRD1764201 to S.R.
Cancer is a leading cause of death in the United States of America and is a complex disease characterized by uncontrolled proliferation of cells. Current cancer therapies are promoting the use of personalized medicine to treat the disease, thus increasing survival rates. Melanoma antigen genes (MAGEs), a subgroup of cancer‐testis antigens (CTAs), are expressed in the male germline and aberrantly in many cancers (Type I) or ubiquitously expressed (Type II). This research focuses on MAGEB2, a virtually understudied Type I MAGE located on the X chromosome. Previous data from our lab indicate that expression of MAGEB2 in normal cells increases cell proliferation, while depletion of MAGEB2 from cancer cells results in lack of cell viability. Based on these data, we hypothesize that MAGEB2 expression provides a proliferative advantage to cancer cells. To determine the signaling pathways modulated by MAGEB2 expression, we performed RNA‐Sequencing on cells expressing MAGEB2 and then identified the most upregulated and downregulated genes with significance to cancer. We will validate our gene expression data and perform gene ontology analysis, followed by gain and loss of function studies to determine signaling pathways required for MAGEB2 to cause a proliferative phenotype. Our second approach will determine the proteins associated with MAGEB2. Using immunoprecipitation (IP)/Mass Spectrometry (MS), we have identified binding partners involved in DNA repair, apoptosis, cell cycle regulation, ribosome biogenesis, chromatin maintenance and remodeling, and protein synthesis. Understanding the mechanisms altering MAGEB2 expression can help scientists develop novel therapeutics to treat cancer.
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