A coherent FOXO3-SNAI2 feed-forward loop in autophagy.

SignificanceUnderstanding autophagy regulation is instrumental in developing therapeutic interventions for autophagy-associated disease. Here, we identified SNAI2 as a regulator of autophagy from a genome-wide screen in HeLa cells. Upon energy stress, SNAI2 is transcriptionally activated by FOXO3 and interacts with FOXO3 to form a feed-forward regulatory loop to reinforce the expression of autophagy genes. Of note, SNAI2-increased FOXO3-DNA binding abrogates CRM1-dependent FOXO3 nuclear export, illuminating a pivotal role of DNA in the nuclear retention of nucleocytoplasmic shuttling proteins. Moreover, a dFoxO-Snail feed-forward loop regulates both autophagy and cell size in Drosophila, suggesting this evolutionarily conserved regulatory loop is engaged in more physiological activities.

Loss of Bicra impairs Drosophila learning and choice abilities.

The Drosophila Bicra (CG11873) gene encodes the sole ortholog of mammalian GLTSCR1 and GLTSCR1L, which are components of a chromatin remodeling complex involved in neoplasia and metastasis of cancer cells. Bicra is highly expressed in Drosophila larval CNS and adult brain, yet its physiological functions in the nervous system remain elusive. Here we report that Bicra is expressed in both neurons and glia of adult brains, and is required for courtship learning and choice ability of male flies. The function of Bicra in the mushroom body, and in particular, Bicra expression in neurons but not glia, is responsible for the male courtship learning and choice performance. This study unravels a novel function of Bicra in cognition-related courtship behaviors in Drosophila, and may provide insight into the neuronal functions of its mammalian orthologs.

Toll-7 promotes tumour growth and invasion in Drosophila.

OBJECTIVES: Drosophila melanogaster has become an excellent model organism to explore the genetic mechanisms underlying tumour progression. Here, by using well-established Drosophila tumour models, we identified Toll-7 as a novel regulator of tumour growth and invasion. MATERIALS AND METHODS: Transgenic flies and genetic epistasis analysis were used. All flies were raised on a standard cornmeal and agar medium at 25°C unless otherwise indicated. Immunostaining and RT-qPCR were performed by standard procedures. Images were taken by OLYMPUS BX51 microscope and Zeiss LSM 880 confocal microscope. Adobe Photoshop 2020 and Zeiss Zen were used to analyse the images. All results were presented in Scatter plots or Column bar graphs created by GraphPad Prism 8.0. RESULTS: Loss of Toll-7 suppresses RasV12 /lgl-/- -induced tumour growth and invasion, as well as cell polarity disruption-induced invasive cell migration, whereas expression of a constitutively active allele of Toll-7 is sufficient to promote tumorous growth and cell migration. In addition, the Egr-JNK signalling is necessary and sufficient for Toll-7-induced invasive cell migration. Mechanistically, Toll-7 facilitates the endocytosis of Egr, which is known to activate JNK in the early endosomes. Moreover, Toll-7 activates the EGFR-Ras signalling, which cooperates with the Egr-JNK signalling to promote Yki-mediated cell proliferation and tissue overgrowth. Finally, Toll-7 is necessary and sufficient for the proper maintenance of EGFR protein level. CONCLUSIONS: Our findings characterized Toll-7 as a proto-oncogene that promotes tumour growth and invasion in Drosophila, which shed light on the pro-tumour function of mammalian Toll-like receptors (TLRs).

Snail regulates Hippo signalling-mediated cell proliferation and tissue growth in Drosophila.

Snail (Sna) plays a pivotal role in epithelia-mesenchymal transition and cancer metastasis, yet its functions in normal tissue development remain elusive. Here, using Drosophila as a model organism, we identified Sna as an essential regulator of Hippo signalling-mediated cell proliferation and tissue growth. First, Sna is necessary and sufficient for impaired Hippo signalling-induced cell proliferation and tissue overgrowth. Second, Sna is necessary and sufficient for the expression of Hippo pathway target genes. Third, genetic epistasis data indicate Sna acts downstream of Yki in the Hippo signalling. Finally, Sna is physiologically required for tissue growth in normal development. Mechanistically, Yki activates the transcription of sna, whose protein product binds to Scalloped (Sd) and promotes Sd-dependent cell proliferation. Thus, this study uncovered a previously unknown physiological function of Sna in normal tissue development and revealed the underlying mechanism by which Sna modulates Hippo signalling-mediated cell proliferation and tissue growth.

CtBP modulates Snail-mediated tumor invasion in Drosophila.

Cancer is one of the most fatal diseases that threaten human health, whereas more than 90% mortality of cancer patients is caused by tumor metastasis, rather than the growth of primary tumors. Thus, how to effectively control or even reverse the migration of tumor cells is of great significance for cancer therapy. CtBP, a transcriptional cofactor displaying high expression in a variety of human cancers, has become one of the main targets for cancer prediction, diagnosis, and treatment. The roles of CtBP in promoting tumorigenesis have been well studied in vitro, mostly based on gain-of-function, while its physiological functions in tumor invasion and the underlying mechanism remain largely elusive. Snail (Sna) is a well-known transcription factor involved in epithelial-to-mesenchymal transition (EMT) and tumor invasion, yet the mechanism that regulates Sna activity has not been fully understood. Using Drosophila as a model organism, we found that depletion of CtBP or snail (sna) suppressed RasV12/lgl-/--triggered tumor growth and invasion, and disrupted cell polarity-induced invasive cell migration. In addition, loss of CtBP inhibits RasV12/Sna-induced tumor invasion and Sna-mediated invasive cell migration. Furthermore, both CtBP and Sna are physiologically required for developmental cell migration during thorax closure. Finally, Sna activates the JNK signaling and promotes JNK-dependent cell invasion. Given that CtBP physically interacts with Sna, our data suggest that CtBP and Sna may form a transcriptional complex that regulates JNK-dependent tumor invasion and cell migration in vivo.

Toll signaling promotes JNK-dependent apoptosis in Drosophila.

BACKGROUND: Apoptosis plays pivotal roles in organ development and tissue homeostasis, with its major function to remove unhealthy cells that may compromise the fitness of the organism. Toll signaling, with the ancient evolutionary origin, regulates embryonic dorsal-ventral patterning, axon targeting and degeneration, and innate immunity. Using Drosophila as a genetic model, we characterized the role of Toll signaling in apoptotic cell death. RESULTS: We found that gain of Toll signaling is able to trigger caspase-dependent cell death in development. In addition, JNK activity is required for Toll-induced cell death. Furthermore, ectopic Toll expression induces the activation of JNK pathway. Moreover, physiological activation of Toll signaling is sufficient to produce JNK-dependent cell death. Finally, Toll signaling activates JNK-mediated cell death through promoting ROS production. CONCLUSIONS: As Toll pathway has been evolutionarily conserved from Drosophila to human, this study may shed light on the mechanism of mammalian Toll-like receptors (TLRs) signaling in apoptotic cell death.

Snail modulates JNK-mediated cell death in Drosophila.

Cell death plays a pivotal role in animal development and tissue homeostasis. Dysregulation of this process is associated with a wide variety of human diseases, including developmental and immunological disorders, neurodegenerative diseases and tumors. While the fundamental role of JNK pathway in cell death has been extensively studied, its down-stream regulators and the underlying mechanisms remain largely elusive. From a Drosophila genetic screen, we identified Snail (Sna), a Zinc-finger transcription factor, as a novel modulator of ectopic Egr-induced JNK-mediated cell death. In addition, sna is essential for the physiological function of JNK signaling in development. Our genetic epistasis data suggest that Sna acts downstream of JNK to promote cell death. Mechanistically, JNK signaling triggers dFoxO-dependent transcriptional activation of sna. Thus, our findings not only reveal a novel function and the underlying mechanism of Sna in modulating JNK-mediated cell death, but also provide a potential drug target and therapeutic strategies for JNK signaling-related diseases.