Cooperation of the BTB-Zinc finger protein, Abrupt, with cytoskeletal regulators in Drosophila epithelial tumorigenesis

Nezaket Turkel; Marta Portela; Carole Poon; Jason Li; Anthony M Brumby; Helena E Richardson

doi:10.1242/bio.012815

Cooperation of the BTB-Zinc finger protein, Abrupt, with cytoskeletal regulators in Drosophila epithelial tumorigenesis

Biol Open. 2015 Jul 17;4(8):1024-39. doi: 10.1242/bio.012815.

Authors

Nezaket Turkel¹, Marta Portela¹, Carole Poon¹, Jason Li², Anthony M Brumby¹, Helena E Richardson³

Affiliations

¹ Cell Cycle and Development Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia.
² Bioinformatics Core Facility, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia.
³ Cell Cycle and Development Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia Sir Peter MacCallum Department of Oncology, Department of Anatomy and Neuroscience, Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria 3010, Australia School of Molecular Sciences, La Trobe University, Melbourne, Victoria 3086, Australia h.richardson@latrobe.edu.au.

Abstract

The deregulation of cell polarity or cytoskeletal regulators is a common occurrence in human epithelial cancers. Moreover, there is accumulating evidence in human epithelial cancer that BTB-ZF genes, such as Bcl6 and ZBTB7A, are oncogenic. From our previous studies in the vinegar fly, Drosophila melanogaster, we have identified a cooperative interaction between a mutation in the apico-basal cell polarity regulator Scribble (Scrib) and overexpression of the BTB-ZF protein Abrupt (Ab). Herein, we show that co-expression of ab with actin cytoskeletal regulators, RhoGEF2 or Src64B, in the developing eye-antennal epithelial tissue results in the formation of overgrown amorphous tumours, whereas ab and DRac1 co-expression leads to non-cell autonomous overgrowth. Together with ab, these genes affect the expression of differentiation genes, resulting in tumours locked in a progenitor cell fate. Finally, we show that the expression of two mammalian genes related to ab, Bcl6 and ZBTB7A, which are oncogenes in mammalian epithelial cancers, significantly correlate with the upregulation of cytoskeletal genes or downregulation of apico-basal cell polarity neoplastic tumour suppressor genes in colorectal, lung and other human epithelial cancers. Altogether, this analysis has revealed that upregulation of cytoskeletal regulators cooperate with Abrupt in Drosophila epithelial tumorigenesis, and that high expression of human BTB-ZF genes, Bcl6 and ZBTB7A, shows significant correlations with cytoskeletal and cell polarity gene expression in specific epithelial tumour types. This highlights the need for further investigation of the cooperation between these genes in mammalian systems.

Keywords: Abrupt; Actin cytoskeletal regulators; Apico-basal cell polarity; BTB-ZF; Drosophila; Eye-antennal disc; Rac1; RhoGEF2; Scribble; Src.