Mutations of genes with a role in chromatin silencing, primarily members of various Polycomb group complexes, have been isolated or characterized as enhancers of hyperproliferative phenotypes (for example, phenotypes produced by activated Notch signaling, an activated Ras mutation, or loss of a Scribble complex component). These include mutations of ph-p, ph-d, and Pc, a double mutation of Psc and Su(z)2, a double overexpression mutation of psq and lola (designated "eyeful"), and reduced function of Sin3A. Reduced function of Sin3A has been observed to exacerbate tumorigenic phenotypes in a number of other fly disease model systems (see FBhh0000013, FBhh0000014, FBhh0000169). Overexpression of Dl combined with overexpression of psq and lola has been described as the "eyeful cancer model."
See also the human disease model reports 'cancer, multiple, Notch signaling pathway' (FBhh0000766), 'cancer, multiple, RAS-related' (FBhh0000474), and 'cancer, epithelial, Scribble-complex-related (FBhh0000586).
Members of SWI/SNF or Brahma-associated chromatin-remodeling complexes in fly have been also studied in the context of cancer disease models, including osa, brm, mor and Snr1; the role of osa has been most thoroughly characterized. Dmel\Snr1 has been used in a disease model of rhabdoid tumor predisposition syndrome (FBhh0000452). brm has been shown to interact with histone deacetylase 3 (HDAC3) to suppress dedifferentiation of type II neuroblasts.
Most loss-of-function mutations of these genes are lethal; somatic clones induced in imaginal discs allow characterization. In typical experiments, clones are generated in such a way that the clone comprises most of the disc cells, reducing effects of cell competition.
A component of the nucleosome remodeling deacetylase (NuRD) complex, Dmel\Mi-2 (orthologous to human CHD3, CHD4, and CHD5), has been used to characterize mutations analogous to disease-implicated variants of CHD4 seen in human cancers. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): C452Y in the fly Mi-2 gene corresponds to C464Y in the human CHD4 gene); H1153R in the fly Mi-2 gene corresponds to H1151R in the human CHD4 gene); R1164Q in the fly Mi-2 gene corresponds to R1162Q in the human CHD4 gene); H1198Y in the fly Mi-2 gene corresponds to H1196Y in the human CHD4 gene); L1217P in the fly Mi-2 gene corresponds to L1215P in the human CHD4 gene).
[updated Nov. 2019 by FlyBase; FBrf0222196]