Moreover, using an in-house generated gene expression dataset, we experimentally proved that a component of the polycomb-repressive complex 2, the histone methyltransferase enhancer of zeste homolog 2 (EZH2), interacts with miR-214, a well-known prometastatic miR in melanoma and breast cancer, highlighting a miR-214-EZH2 regulatory axis potentially relevant in tumor progression.
Recently, EZH2 was shown to control mechanisms of adaptive resistance to immunotherapy in melanoma; however, the association between EZH2 and programmed death-ligand 1 (PD-L1), which reflects the tumor microenvironment, remains poorly understood.
In this issue of Cancer Cell, Zingg et al. find that EZH2 overexpression silences genes for the primary cilium, causing deciliation, Wnt pathway activation, and progression of Braf<sup>V600E</sup>- or Nras<sup>Q61N</sup>-driven melanomas, thus defining a tumor-suppressor role for cilia in cancer.
Overall, the present study demonstrated that the lncRNA PVT1 may contribute to the tumorigenesis and metastasis of melanoma through binding to EZH2 and regulating the expression of miR‑200c. lncRNA PVT1 may serve as a potential target for the therapy of melanoma.
In addition, we have identified a set of SCNAs, including amplification of BRAF and ofthe epigenetic modifier EZH2, that are specific for the group of thick melanomas that developed metastasis during the follow-up.
This is the first study focusing on the detailed epigenetic mechanisms leading to EZH2-mediated silencing of RUNX3 and E-cadherin tumor suppressors in melanoma.
Finally, we show in mouse models that the inhibition of the non-canonical NF-kB pathway restores senescence and induces a dramatic reduction in tumor growth compared with controls, thus providing potential drug targets for the re-induction of senescence in melanoma and other cancers where EZH2 is overexpressed.
These results suggest that Ezh2(Y641F) induces lymphoma and melanoma through a vast reorganization of chromatin structure, inducing both repression and activation of polycomb-regulated loci.
This study not only demonstrates the first functional characterization of EZH2 GOF mutants in non-hematopoietic cells, but also provides a rationale for EZH2 catalytic inhibition in melanoma.
In the following review, we discuss the evidence that EZH2 is an important driver of melanoma progression and we summarize the progress of EZH2 inhibitors against this promising therapeutic target.
Heterogeneity of EZH2 levels is observed in melanoma models, and co-ordinated upregulation of genes positively regulated by EZH2 is associated with melanoma metastasis.
These results emphasize a critical role for EZH2 in the proliferation and viability of melanoma and highlight the potential for targeted therapy against EZH2 in treatment of patients with melanoma.
Highest EZH2 activation is seen in neuroblastoma, hepatocellular carcinoma, small cell lung cancer, and melanoma, while highest HDAC activity is seen in pharyngeal cancer, kidney cancer, and pancreatic cancer.
Furthermore, miR-31 overexpression resulted in down-regulation of EZH2 and a de-repression of its target gene rap1GAP; increased expression of EZH2 was associated with melanoma progression and overall patient survival.