Abstract
ABSTRACTSwitch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complexes are mutated in many human cancers. In this article, we make use of a Drosophila genetic model for epithelial tumor formation to explore the tumor suppressive role of SWI/SNF complex proteins. Members of the BAP complex exhibit tumor suppressor activity in tissue overexpressing the Yorkie (Yki) proto-oncogene, but not in tissue overexpressing epidermal growth factor receptor (EGFR). The Brahma-associated protein (BAP) complex has been reported to serve as a Yki-binding cofactor to support Yki target expression. However, we observed that depletion of BAP leads to ectopic expression of Yki targets both autonomously and non-autonomously, suggesting additional indirect effects. We provide evidence that BAP complex depletion causes upregulation of the Wingless (Wg) and Decapentaplegic (Dpp) morphogens to promote tumor formation in cooperation with Yki.
Highlights
Tumors accumulate multiple genetic and epigenetic modifications, and mutations in epigenetic regulators are associated with several types of human cancer
SWI/SNF chromatin remodeling complexes are mutated in many human cancers
We provide evidence that BAP complex depletion causes upregulation of the Wingless and Dpp morphogens to promote tumor formation in cooperation with Yki
Summary
Tumors accumulate multiple genetic and epigenetic modifications, and mutations in epigenetic regulators are associated with several types of human cancer. Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are the nuclear effectors of the Hippo pathway, and regulate organ growth and are potent drivers of tumor formation (Harvey et al, 2013; Johnson and Halder, 2014; Piccolo et al, 2014; Yu et al, 2015). Even though activation of the YAP and TAZ are wide spread in human cancers, much remains to be learned about other factors that may cooperate with these oncogenes to promote malignant tumor formation. SWI/SNF chromatin remodeling complexes are among the most commonly mutated genes in human cancer and have a crucial role in tumor suppression (Kadoch et al, 2013; Wilson and Roberts, 2011). Specific mechanisms by which SWI/SNF complexes suppress tumor formation remain poorly understood. Subunits of the SWI/SNF complex have been shown to play a tumor suppressive role in Drosophila (Eroglu et al, 2014; Koe et al, 2014; Xie et al, 2017)
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