Ectopic Expression of Zmiz1 Induces Cutaneous Squamous Cell Malignancies in a Mouse Model of Cancer

Cutaneous squamous cell carcinoma (SCC) is the second most common form of cancer in the human population, yet the underlying genetic mechanisms contributing to the disease are not well understood. We recently identified Zmiz1 as a candidate oncogene in nonmelanoma skin cancer through a transposon mutagenesis screen. Here we show that transposon-induced mutations in Zmiz1 drive expression of a truncated transcript that is similar to an alternative endogenous ZMIZ1 transcript found to be overexpressed in human SCCs relative to normal skin. We also describe an original mouse model of invasive keratoacanthoma driven by skin-specific expression of the truncated Zmiz1 transcript. Unlike most mouse models, Zmiz1-induced skin tumors develop rapidly and in the absence of promoting agents such as phorbol esters. In addition, we found that the alternative Zmiz1 isoform has greater protein stability than its full-length counterpart. Finally, we provide evidence that ZMIZ1 is overexpressed in a significant percentage of human breast, ovarian, and colon cancers in addition to human SCCs, suggesting that ZMIZ1 may play a broader role in epithelial cancers.