The chromatin remodeling BAP complex limits tumor promoting activity of the Hippo pathway effector Yki to prevent neoplastic transformation inDrosophilaepithelia

Abstract

Switch/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.

Genome-wide RNAi screen for context-dependent tumor suppressors identified using in vivo models for neoplasia in Drosophila

“…Under these conditions the imaginal discs retain normal epithelial organization, but grow considerably larger than normal. However, in combination with additional genetic or environmental changes, the tissue can become neoplastic and form malignant tumors [8,9,22] [28].…”

“…Supplemental Table S1(A) lists the genes identified in these three screens. In previous studies, massive disc overgrowth as in Figure 1 [22]. Apico-basal polarity and Matrix Metalloprotease 1 (MMP1) expression were assessed for a randomly selected subset of lines from the EGFR and Yki screens to assess neoplastic transformation ( Figure S1 and Table S1 -second sheet).…”

“…In vivo functional screens using transposon mutagenesis of the mouse genome have begun to identify mutations that cooperate with known cancer driver mutations, such as K-Ras, in specific tumor models [15][16][17]. Genetic approaches using Drosophila models of oncogene cooperation have also been used to identify genes that act together with known cancer drivers in tumor formation [8,9,[18][19][20] [21,22] [2, 23]. The simplicity of the Drosophila genome, coupled with the ease of large-scale genetic screens and the high degree of conservation of major signaling pathways with humans, make Drosophila an interesting model to identify novel cancer genes and to study the cellular and molecular mechanisms that underlie tumor formation in vivo (reviewed in [24][25][26][27]).…”

“…Combining these with additional genetic alterations can lead to neoplastic transformation and eventually metastasis [8,9,21,22] [28]. Here, we report results of large-scale screens combining UAS-RNAi transgenes with EGFR or Yki expression to identify negative regulators of these growth regulatory networks that can lead to aggressive tumor formation in vivo.…”

RhoBTB Proteins Regulate the Hippo Pathway by Antagonizing Ubiquitination of LKB1

“…The use of Drosophila imaginal wing discs as a model for epithelial tumor formation was previously described (Herranz et al 2012;Song et al 2017;. RhoBTB was a validated candidate from a genome-wide screen identifying tumor suppressors whose knockdown promoted oncogenic activity of Yki as a tumor driver in Drosophila (Groth et al 2019 preprint).…”