The histone demethylase KDM3A, and its downstream target MCAM, promote Ewing Sarcoma cell migration and metastasis

Abstract

Ewing Sarcoma is the second most common solid pediatric malignant neoplasm of bone and soft tissue. Driven by EWS/Ets, or rarely variant, oncogenic fusions, Ewing Sarcoma is a biologically and clinically aggressive disease with a high propensity for metastasis. However, the mechanisms underpinning Ewing Sarcoma metastasis are currently not well understood. In the present study, we identify and characterize a novel metastasis-promotional pathway in Ewing Sarcoma, involving the histone demethylase KDM3A, previously identified by our laboratory as a new cancer-promoting gene in this disease. Using global gene expression profiling, we show that KDM3A positively regulates genes and pathways implicated in cell migration and metastasis, and demonstrate, using functional assays, that KDM3A promotes migration in vitro and experimental, post-intravasation, metastasis in vivo. We further identify the Melanoma Cell Adhesion Molecule (MCAM) as a novel KDM3A target gene in Ewing Sarcoma, and an important effector of KDM3A pro-metastatic action. Specifically, we demonstrate that MCAM depletion, like KDM3A depletion, inhibits cell migration in vitro and experimental metastasis in vivo, and that MCAM partially rescues impaired migration due to KDM3A knock-down. Mechanistically, we show that KDM3A regulates MCAM expression both through a direct mechanism, involving modulation of H3K9 methylation at the MCAM promoter, and an indirect mechanism, via the Ets1 transcription factor. Lastly, we identify an association between high MCAM levels in patient tumors and poor survival, in two different Ewing Sarcoma clinical cohorts. Taken together, our studies uncover a new metastasis-promoting pathway in Ewing Sarcoma, with therapeutically targetable components.

LncRNA H19 ameliorates myocardial infarction‐induced myocardial injury and maladaptive cardiac remodelling by regulating KDM3A

“…However, the opposite was true in KDM3A‐knockout rats. We and others have found that ETS‐1 is a downstream target of KDM3A, and our latest experiment verified that KDM3A could directly bind to the promoter of ETS‐1 and control H3K9 methylation in myocardial ischaemia‐reperfusion injury. KDM3A overexpression displayed higher ETS‐1 transcriptional activity concomitant with reduced inflammation, ROS and apoptosis.…”

METCAM/MUC18 Promotes Tumor Progression and Metastasis in Most Human Cancers

“…Having a longer DNA containing sequences for tissue-specific expression of the gene is essential for further understanding the roles of other regulators [17]. In line with this hypothesis, recently, the Ets sequence in the 10 kilo-bp upstream region has been shown to regulate the expression of huMET-CAM/MUC18 gene [95]. We have also engaged in this task by screening in a phage library containing the human genomic sequences and obtained several phage clones which contain at least 4 kilo-bp of in the upstream region of the promoter region of the gene for future studies [96].…”

The potential of KDM3A as a therapeutic target in Ewing Sarcoma and other cancers

“…Recently, a number of studies have implicated KDM3A (JMJD1A/JHDM2A), a member of the KDM3 subfamily with specificity for removal of mono and di-methyl marks from H3K9, in tumor/metastasis promotion, chemoresistance and other phenotypes, in cancers of epithelial origin (including the common cancers of breast 4 , prostate 5 and colon 6 ), liver 7 , and the hematopoietic system 8 . Additionally, recent studies have implicated KDM3A in solid malignancies of childhood, including the metastasis of neuroblastoma 9 , a malignant pediatric tumor of peripheral nervous system origin, and both tumorigenesis and metastasis of Ewing Sarcoma 10, 11 , a pediatric sarcoma of bone and soft tissue.…”

“…The biology of Ewing Sarcoma metastasis is incompletely understood and, surprisingly, recent studies indicate that the driver oncofusion, EWS/Fli1, attenuates rather than augments metastatic properties of the cancer 12, 13 . The biology of KDM3A is very interesting in this context, in that it positively regulates many pro-metastatic genes repressed by EWS/Fli1 11 . As a promoter of tumorigenesis and metastasis, KDM3A is a therapeutic target of interest in Ewing Sarcoma.…”

“…Approaches could entail similar targeting of key intermolecular interactions or an enzymatic activity of a critical co-factor. Alternatively, one could focus on key druggable downstream mediators of KDM3A action, such as the cell surface molecules CD44 in hepatocellular carcinoma 7 and MCAM in Ewing Sarcoma 11 , which could be inhibited using blocking antibodies. Further understanding of KDM3A biology in cancer should inform optimal approaches to therapeutic targeting.…”