We conclude that a combination of GD specific CAR

We conclude that a combination of GD2-specific CAR T cell therapy with pharmacological EZH2 inhibition deserves investigation as a new therapeutic strategy in EwS and potentially other cancers with heterogeneous GD2 expression, including osteosarcoma, various soft tissue sarcomas, melanoma, lung cancer, and breast cancer. Re-biopsies or repeated GD2 antibody scans of EwS patients treated with EZH2 inhibitors would be highly informative to confirm the effects of EZH2 inhibitors on GD2 expression levels and their tumor selectivity in patients. Studying epigenetic regulation of carbohydrate antigen expression in cancer could lead to additional combination strategies also for other non-protein CAR target antigens.
Materials and Methods
Author Contributions
Conflicts of Interest Westfälische Wilhelms-Universität Münster (WWU) has filed a patent with S.K., B.A., and C.R. as inventors composing GD2 upregulation by EZH2 inhibition in cancer.
Acknowledgments We thank Natalia Moreno, Claudia Lanvers-Kaminsky, Marc Hotfilder, Annegret Rosemann, Anne Kruchen, Kerstin Cornils, Daniela Schwammbach, and Vijay Bhaskar Reddy for helpful contributions. This work was funded by grant RO 2402/6-1 from the Deutsche Forschungsgemeinschaft (DFG), Germany (to C.R.) and by Kinderkrebshilfe Münster e.V.
Introduction As one of the most common and aggressive human malignancies, Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide [1,2]. The poor prognosis and high recurrence rate of HCC is largely due to the high rate of intrahepatic and extrahepatic metastases [3]. For advanced hepatocellular carcinoma, the only first-line drug is sorafenib, which unfortunately has a limited effect on hepatocellular carcinoma metastases [4,5]. Metastasis is a complex process, and many cell-intrinsic identities and extrinsic microenvironment factors influence the metastatic potential of HCC CTX0294885 australia [6,7]. However, the molecular mechanisms underlying the development and progression of HCC metastatic cascade remain poorly understood. Enhancing our understanding of the molecular mechanisms may promote the development of effective metastasis-targeted therapy and improve the overall prognosis of patients with HCC. MicroRNA (miRNA), a class of endogenous small non-coding RNA that bind the complementary coding sequences of the 3′-untranslated regions (3′-UTR) of downstream target genes, has increasingly been recognized as an important post-transcriptional gene regulator [8,9]. In the past decades, thousands of miRNAs have been discovered and annotated in the human and vertebrate genomes. These miRNAs are participating in almost all major cellular processes in cancers, such as cellular differentiation, proliferation, migration and apoptosis. MicroRNA-137, also called miR-137, is often found to be downregulated, and acting as tumor suppressors by inhibiting cancer proliferation, cell-cycle progression, or migration in various types of human cancers, such as lung cancer, colorectal cancer, gastric cancer, or cervical cancer [[10], [11], [12], [13]]. However, how miR-137 involved in the metastasis progression in human HCC remains unclear. Human gene of enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and is the catalytic subunit of polycomb repressive complex 2, a highly conserved protein complex that regulates gene expression by methylating lysine 27 on histone H3 [14]. In recent decades, emerging evidence has demonstrated that EZH2 is an active epigenetic regulator in human cancer, especially promote liver cancer metastasis by epigenetically silencing multiple tumor suppressor [15]. In addition, EZH2 has been demonstrated to regulate cancer development through the association with miRNAs, such as miR-137, in glioblastoma, neuroblastoma, or non-small cell lung cancer [16,17]. However, it is still unclear of the molecular mechanism underlying the role of miR-137/EZH2 attributing to HCC metastasis. In this study, we revealed that miR-137 suppressed invasion by targeting EZH2-STAT3 signaling in human hepatocellular carcinoma. Our results suggest that miR-137 decreasing contributes to tumor metastasis through EZH2-STAT3 signaling in human hepatocellular carcinoma cells, and that miR-137-EZH2-STAT3 is therefore a potential therapeutic target for treatment of human hepatocellular carcinoma.