Abstract
Approximately 90% of cancer-related deaths can be attributed to a tumour's ability to spread. We have identified CG7379, the fly orthologue of human ING1, as a potent invasion suppressor. ING1 is a type II tumour suppressor with well-established roles in the transcriptional regulation of genes that control cell proliferation, response to DNA damage, oncogene-induced senescence and apoptosis. Recent work suggests a possible role for ING1 in cancer cell invasion and metastasis, but the molecular mechanism underlying this observation is lacking. Our results show that reduced expression of CG7379 promotes invasion in vivo in Drosophila, reduces the junctional localization of several adherens and septate junction components, and severely disrupts cell-cell junction architecture. Similarly, ING1 knockdown significantly enhances invasion in vitro and disrupts E-cadherin distribution at cell-cell junctions. A transcriptome analysis reveals that loss of ING1 affects the expression of several junctional and cytoskeletal modulators, confirming ING1 as an invasion suppressor and a key regulator of cell-cell junction integrity.
Highlights
Metastasis is the major cause of mortality in human cancers
Using an antibody against human E-cadherin on the breast cancer cell line MCF7, we found a significant disruption to both E-cadherin localization and to AJ integrity following ING1KD, with frequent junctional breaks observed, suggesting that human ING1 plays an important role in maintaining AJ integrity
The in vivo model for epithelial cancer that we have developed has proven to be suitable for the study of cancer cell invasion
Summary
Metastasis is the major cause of mortality in human cancers. Underlying this phenomenon are a number of highly complex cellular behaviours, whereby cancer cells must acquire an ability to invade out of the primary tumour mass, avoid anoikis, migrate directionally and disseminate to form secondary tumours at distant secondary sites. We have developed an in vivo system in Drosophila that allows the study of epithelial cell and tissue morphogenesis in real time [1,2,3,4] We recently used this system to generate tumours with specific genotypes on the dorsal thorax epithelium of the fly and to screen for conserved modulators of tumour behaviour in the living animal [5]. This screen allowed the identification of numerous invasion suppressors, one of which was the Drosophila inhibitor of growth (ING) orthologue CG7379
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