Abstract
The mechanism for Myc-induced genetic instability is not well understood. Here we show that sublethal activation of Caspase-3 plays an essential, facilitative role in Myc-induced genomic instability and oncogenic transformation. Overexpression of Myc resulted in increased numbers of chromosome aberrations and γH2AX foci in non-transformed MCF10A human mammary epithelial cells. However, such increases were almost completely eliminated in isogenic cells with CASP3 gene ablation. Furthermore, we show that endonuclease G, an apoptotic nuclease downstream of Caspase-3, is directly responsible for Myc-induced genetic instability. Genetic ablation of either CASP3 or ENDOG prevented Myc-induced oncogenic transformation of MCF10A cells. Taken together, we believe that Caspase-3 plays a critical, unexpected role in mediating Myc-induced genetic instability and transformation in mammalian cells.
Highlights
One of the hallmarks of cancer is increased genomic instability (Hanahan and Weinberg, 2011)
We show sublethal activation of caspase 3 and endonuclease G plays an essential role in Myc-induced genetic instability and oncogenic transformation in human cells
6% of Myc-expressing MCF10A cells were observed with having relatively normal nuclei and cleaved caspase 3, as compared to control MCF10A cells where only ~1% of the cells were observed with cleaved caspase 3
Summary
One of the hallmarks of cancer is increased genomic instability (Hanahan and Weinberg, 2011). High levels of Myc proteins in a cell can activate proteins that trigger a process called apoptosis, which makes the cell commit suicide. Caspase-3 triggers a series of events that lead to apoptosis, while endonuclease G cuts up DNA in preparation for cell death It is not known how these proteins affect the cancerpromoting properties of Myc. Here, Cartwright, Liu et al used a gene editing technique called CRISPR-Cas to examine how these apoptosis proteins affect the ability of Myc to promote cancer. We show sublethal activation of caspase 3 and endonuclease G plays an essential role in Myc-induced genetic instability and oncogenic transformation in human cells
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