H3K27me3 and EZH2 expression in melanoma: relevance for melanoma progression and response to immune checkpoint blockade

Abstract

Background: Upregulation of the histone methyltransferase enzyme EZH2 and its histone modification H3K27me3 has been linked to melanoma progression, metastasis, and resistance to immune checkpoint blockade (ICB). In clinical trials, EZH2 inhibitors are currently tested to overcome resistance to ICB. The aim of this study is to evaluate expression patterns and the predictive value of H3K27me3 and EZH2 in metastatic melanoma samples prior to ICB. As H3K27me3 expression has been associated with a dedifferentiated, invasive melanoma phenotype, we also investigated the prognostic value of H3K27me3 expression in primary melanomas. Results: H3K27me3 and EZH2 expression were evaluated in a cohort of 44 metastatic melanoma samples before ICB using immunohistochemistry (IHC). 29/44 (66%) of melanomas showed H3K27me3 expression, and 6/44 (14%) showed EZH2 expression. No predictive value for therapeutic response to anti-PD-1 therapy could be found for H3K27me3 or EZH2 expression on melanoma cells. To investigate the prognostic significance of H3K27me3, we analyzed H3K27me3 expression in a representative cohort of 136 primary melanomas with known sentinel lymph node status. H3K27me3 expression is associated with increased tumor thickness and nodal involvement. Melanoma metastases showed a higher expression of H3K27me3 in comparison to primary melanomas. In human melanoma cell lines, TNFα and INFγ could not induce H3K27me3 expression. Conclusion: Our study shows that H3K27me3 expression is more frequent than EZH2 and is associated with a more invasive and metastatic melanoma cell phenotype. We suggest that H3K27me3 expression by IHC might be a suitable method to evaluate the activity of EZH2 inhibitors in clinical trials.

Loss of H3K27 methylation identifies poor outcomes in adult-onset acute leukemia

“…Our data supports that proteomic profiling of histone methylation levels improves outcome prediction in AML and Ph+ ALL and suggest potential targets to further investigate diagnostically and therapeutically. H3K27me3 loss associates with tumor aggressiveness and patient outcomes in numerous cancers [ 10 – 16 ], similar as we found in AML.…”

“…Epigenetic dysregulation by histone protein modifications is also well-recognized to play a role in tumor development. Loss of the repressive mark H3K27me3 has been reported in breast, colon, ovarian, pancreatic, prostate, nervous system tumors and melanoma [ 10 – 16 ]. H3K4 di- and trimethylation are associated with open and active chromatin and are predictive factors for outcome in different cancers with low expression of H3K4me2 being associated with poor outcome in prostate, kidney and lung cancer and high expression of H3K4me3 in liver and cervical cancer [ 17 , 18 ].…”

Genetic Alterations in the INK4a/ARF Locus: Effects on Melanoma Development and Progression

“…The co-operative binding of PRC1 (including the BMI1 subunit) and the long noncoding RNA ANRIL to H3K27me3 compacts the CDKN2A genomic locus and represses transcription [ 25 , 30 , 31 , 32 ], in particular the transcription of p16 INK4a [ 33 ]. In line with these data, the levels of H3K27me3 increase from primary to metastatic melanoma, and high H3K27me3 is an independent poor prognostic marker in melanoma [ 34 , 35 ].…”

Downregulation of MEG3 promotes neuroblastoma development through FOXO1-mediated autophagy and mTOR-mediated epithelial-mesenchymal transition

“…The polycomb repressor complex 2 (PRC2) core component molecule EZH2 has been reported to be important in biological processes, such as the cell cycle, cell differentiation, and carcinoma progression [40,41]. Previous studies showed that EZH2 was significantly increased in NB and negatively associated with NB prognosis [42].…”