EMT as the ultimate survival mechanism of cancer cells.

Polycomb group (PcG) proteins such as Enhancer of zeste homolog 2 (EZH2) are epigenetic transcriptional repressors that function through recognition and modification of histone methylation and chromatin structure. Targets of PcG include cell cycle regulatory proteins which govern cell cycle progression and cellular senescence. Senescence is a characteristic of melanocytic nevi, benign melanocytic proliferations that can be precursors of malignant melanoma. In this study, we report that EZH2, which we find absent in melanocytic nevi but expressed in many or most metastatic melanoma cells, functionally suppresses the senescent state in human melanoma cells. EZH2 depletion in melanoma cells inhibits cell proliferation, restores features of a cellular senescence phenotype, and inhibits growth of melanoma xenografts in vivo. p21/CDKN1A is activated upon EZH2 knockdown in a p53-independent manner and contributes substantially to cell cycle arrest and induction of a senescence phenotype. EZH2 depletion removes histone deacetylase 1 (HDAC1) from the CDKN1A transcriptional start site and downstream region, enhancing histone 3 acetylation globally and at CDKN1A. This results in recruitment of RNA polymerase II, leading to p21/CDKN1A activation. Depletion of EZH2 synergistically activates p21/CDKN1A expression in combination with the HDAC inhibitor trichostatin A. Since melanomas often retain wild-type p53 function activating p21, our findings describe a novel mechanism whereby EZH2 activation during tumor progression represses p21, leading to suppression of cellular senescence and enhanced tumorigenicity.

https://mcr.aacrjournals.org/content/molcanres/9/4/418.full.pdf

EZH2-Dependent Suppression of a Cellular Senescence Phenotype in Melanoma Cells by Inhibition of p21/CDKN1A Expression

Approximately 33% of melanomas are derived directly from benign, melanocytic nevi. Despite this, the vast majority of melanocytic nevi, which typically form as a result of BRAFV600E-activating mutations, will never progress to melanoma. Herein, we synthesize basic scientific insights and data from mouse models with common observations from clinical practice to comprehensively review melanocytic nevus biology. In particular, we focus on the mechanisms by which growth arrest is established after BRAFV600E mutation. Means by which growth arrest can be overcome and how melanocytic nevi relate to melanoma are also considered. Finally, we present a new conceptual paradigm for understanding the growth arrest of melanocytic nevi in vivo termed stable clonal expansion. This review builds upon the canonical hypothesis of oncogene-induced senescence in growth arrest and tumor suppression in melanocytic nevi and melanoma.

Melanocytic nevi and melanoma: unraveling a complex relationship.

Senescence and quiescence are frequently used as interchangeable terms in the literature unwittingly. Despite the fact that common molecules play role in decision of cell cycle arrest, senescent and quiescent cells have some distinctive phenotypes at both molecular and morphological levels. Thus, in this review we summarized the features of senescence and quiescence with respect to visual characteristics and prominent key molecules. A PubMed research was conducted for the key words; "senescence", "quiescence" and "cell cycle arrest". The results which are related to cell cycle control were selected. The selection criteria of the target articles used for this review included also key cell cycle molecules such as p53, pRB, p21, p16, mTOR, p27, etc. The results were not evaluated statistically. The mechanistic target of rapamycin (mTOR) has been claimed to be key molecule in switching on/off senescence/quiescence. Specifically, although maximal p53 activation blocks mTOR and causes quiescence, partial p53 activation sustains mTOR activity and causes senescence subsequently. In broader perspective, quiescence occurs due to lack of nutrition and growth factors whereas senescence takes place due to aging and serious DNA damages. Contrary to quiescence, senescence is a degenerative process ensuing a certain cell death. We highlighted several differences between senescence and quiescence and their key molecules in this review. Whereas quiescence (cell cycle arrest) is only one half of the senescence, the other half is growth stimulation which causes actual senescence phenotype.

The cell fate: senescence or quiescence

Metastasis accounts for the vast majority of morbidity and mortality associated with melanoma Evidence suggests melanoma has a predilection for metastasis to particular organs Experimental analyses have begun to shed light on the mechanisms regulating melanoma metastasis and organ specificity, but these analyses are complicated by observations of metastatic dormancy and dissemination of melanocytes that are not yet fully malignant Additionally, tumor extrinsic factors in the microenvironment, both at the site of the primary tumor and the site of metastasis, play important roles in mediating the metastatic process As metastasis research moves forward, paradigms explaining melanoma metastasis as a step-wise process must also reflect the temporal complexity and heterogeneity in progression of this disease Genetic drivers of melanoma as well as extrinsic regulators of disease spread, particularly those that mediate metastasis to specific organs, must also be incorporated into newer models of melanoma metastasis

https://www.mdpi.com/2072-6694/3/1/126/pdf

Decoding Melanoma Metastasis

Oncogene-induced senescence (OIS) is a robust and sustained antiproliferative response brought about by oncogenic signaling resulting from an activating mutation of an oncogene, or the inactivation of a tumor-suppressor gene. The pathways mediating OIS are complex and incompletely elucidated but, the proliferative arrest involves activation of both the RB and p53 pathways. In addition, whereas there are indications that at least in some situations, negative feedback loops abolish the increased mitogenic signaling resulting from the oncogenic mutations, also an unexpected contribution of interleukin-mediated signaling has recently been found. OIS brings about cessation of growth of some benign tumors, including melanocytic nevi and several other lesions, including pituitary and thyroid adenomas. It protects against progression to cancer, and in this way complements oncogene-induced apoptosis. Perhaps, OIS has evolved as an alternative to apoptosis especially regarding long-lived cell types that are not replaceable in large numbers. Contrary to the earlier belief, OIS is not entirely irreversible, at least in some well documented in vitro systems. This means that its induction does not entirely eliminate the oncogenic threat resulting from the mutated cell. It also means that OIS, or related phenomena that may affect a proportion of the tumor cells of some cancers, may have an influence on responsiveness to cytotoxic cancer therapies, because OIS is associated with an antiapoptosis phenotype.

Charlotte Chandeck

Papers

Oncogene-induced cellular senescence.