Potential Role of Meiosis Proteins in Melanoma Chromosomal Instability

Abstract

Melanomas demonstrate chromosomal instability (CIN). In fact, CIN can be used to differentiate melanoma from benign nevi. The exact molecular mechanisms that drive CIN in melanoma have yet to be fully elucidated. Cancer/testis antigens are a unique group of germ cell proteins that are found to be primarily expressed in melanoma as compared to benign nevi. The abnormal expression of these germ cell proteins, normally expected only in the testis and ovaries, in somatic cells may lead to interference with normal cellular pathways. Germ cell proteins that may be particularly critical in CIN are meiosis proteins. Here, we review pathways unique to meiosis with a focus on how the aberrant expression of meiosis proteins in normal mitotic cells “meiomitosis” could impact chromosomal instability in melanoma and other cancers.

Meiosis-like Functions in Oncogenesis: A New View of Cancer

“…31). While it is unknown whether this REC8 expression resulted in the production of REC8 protein in these somatic tissues, others have indicated REC8 is present in noncancerous cultured cells (9); this might suggest that terminally differentiated human cells do not have such a tight requirement to constrain expression of meiotic genes as actively dividing cells, such as cultured fission yeast cells (i.e., there is no need for a strict Mmi1-like system in terminally differentiated cells). Given that such cells are largely nonproliferative in adult somatic tissue, it is assumed that expression of genes such as REC8 would have little/no influence on ploidy (although cohesins have been implicated in other processes, such as DNA damage recovery and transcriptional control; refs.…”

“…These chromosomal segregation events differ considerably to those of the first meiotic division during gametogenesis, where homologous chromosomes of a diploid germline progenitor cell conjoin via programmed genetic recombination intermediates to form a bivalent, which is ultimately resolved, culminating in a reductional chromosome segregation event and "shuffled" genetic material (2,3). There is now solid emerging evidence to support the concept that the inappropriate activation of meiotic chromosome regulator genes in mitotically dividing somatic cells results in deviations in mechanisms controlling chromosome maintenance and segregation (4)(5)(6)(7)(8)(9).…”

Bcl2l10, a new Tpx2 binding partner, is a master regulator of Aurora kinase A in mouse oocytes

“…45,46 Interestingly, oocytes have been reported to share common characteristics with cancer cells, and meiosis-specific proteins that are restrictively expressed in ovaries or testis have long been observed in cancer cells. 47,48 Oocytes, similar to cancer cells, show a certain degree of aneuploidy when they are unable to sort and cluster MTOCs. 48 Therefore, we presumed that Bcl2l10 plays an important role in controlling the rate of aneuploidy by regulating MTOC clustering in the oocytes.…”

Genome management and mismanagement—cell-level opportunities and challenges of whole-genome duplication

“…Other meiosis proteins expressed in cancer cells REC8: A kleisin important for preventing premature sister chromatid separation in meiosis I. REC8 tethers the cohesin complexes to the centromeres of sister chromatids, effectively gluing them together until meiosis II. Its expression in mitosis could cause chromosome missegregation by preventing proper sister chromatid separation (Ishiguro et al 2010;Lindsey et al 2013;Strunnikov 2013). REC8 may also drive depolyploidization in polyploid cancer cells by promoting reductional divisions (Kalejs et al 2006).…”

“…Although this process is not a true reduction division, it merits discussion here because it highlights why somatic reduction divisions might commonly be unstable. The concept of "meiomitosis" comes from observations that aggressive cancers with high levels of aneuploidy often express one or a few meiosis genes (for review, see Old 2001;Simpson et al 2005;Kalejs et al 2006;Lindsey et al 2013). Examples of several of these genes as well as their intriguing overlap with some of the genes implicated in adaption to polyploidy in A. arenosa are listed in Box 2.…”