SINHA, P. | bioRxiv Science

bioRxiv2023

Hippo effector, Yorkie, is a Tumor Suppressor in Select Drosophila Squamous Epithelia

Out-of-context gain of nuclear signaling of mammalian YAP/TAZ or Drosophila Yki--the transcription cofactors of the highly conserved Hippo tumor suppressor pathway--is oncogenic. By contrast, in mechanically strained squamous epithelia (SE), YAP/TAZ/Yki displays developmentally programmed nuclear translocation, leading to its constitutive signaling. How organ homeostasis is maintained in constitutively YAP/TAZ/Yki signaling SE is unclear. Here, we show that Yki signaling negatively regulates the cell growth-promoting PI3K/Akt/TOR signaling in the SEs in the tubular organs of Drosophila. Thus, in the adult male accessory gland (MAG), knockdown of Yki signaling upregulates PI3K/Akt/TOR signaling in its SE-lined lumen, inducing cell hypertrophy, culminating in squamous cell carcinoma (SCC). MAG SCC-bearing adults display early mortality due to cancer cachexia, which is reversed by simultaneous knockdown of a secreted factor, ImpL2--a Drosophila homolog of mammalian IGFBP7--without arresting tumor progression per se. By contrast, a knockdown of PI3K/Akt/TOR signaling suppresses MAG SCC, reversing adult mortality. In the SE-lined lumens in other tubular organs, like the dorsal trunk of larval tracheal airways or adult Malpighian tubules, too, knockdown of Yki signaling triggers PI3K/Akt/TOR-induced cell hypertrophy and loss of epithelial homeostasis, culminating in their tumor-like transformation. Thus, Yki signaling turns tumor suppressive in the SEs of tubular organs in Drosophila by arresting runaway PI3K/Akt/TOR signaling.

cancer biology↗

bioRxiv2022

Human ERG Oncoprotein Represses Chip/LDB1 LIM-Domain Binding Gene in Drosophila

ERG oncoprotein, a master transcription factor, targets diverse arrays of genes in different cancers. Identifying oncogenically relevant ones from these ERG targets, however, is challenging. Here we show that heterologous ERG disrupts a LIM-homeodomain (LIM-HD) complex, Chip-Tailup, in Drosophila. In the posterior thorax (notum) primordium, ERG-induced upregulation of E(z)/EZH2 trimethylates histones in Chip promoter. A consequent loss of the Chip-Tailup complex releases repression of N-Wg signaling in the notum, inducing de novo wings and, alternatively, carcinogenesis of ERG-expressing notal cells displaying loss of Lgl tumor suppressor. ERG-induced developmental or oncogenic fallouts are abrogated upon gain of Chip, N, or E(z) loss, besides Wg ligand sequestration. ERG-positive prostate cancer (PCa) cells, too, display suppression of mammalian homolog of Drosophila Chip, LIM Domain Binding1, LDB1. Deep homology in gene regulatory networks, like that of Chip-Tup complex, thus help prioritize identification of functionally relevant targets of human oncoproteins in Drosophila. HighlightsO_LIHuman ERG suppresses Chip, a LIM-domain binding, LDB gene in Drosophila via E(z) C_LIO_LIERG-mediated Chip loss induces ectopic Wg morphogen signaling in the notum primordium C_LIO_LIChip gain suppresses ERG-induced Wg morphogen and tumor progression in lgl clones C_LIO_LIERG-positive human PCa cell lines show downregulation of a Chip homolog, LDB1 C_LI In briefMammalian ERG oncoprotein displays a diverse and perplexing range of targets in different cancers. By driving ERG in Drosophila developing appendages, Bharti et al. reveal its repression of a LIM-domain coding gene, Chip/LDB1. ERG-positive prostate cancer cells, too, display Chip/LDB1 repression. Deep homology across phylogeny thus helps uncover oncoprotein targets.

developmental biology↗