Unscheduled overexpression of human WAPL promotes chromosomal instability.

Previously, we have isolated and characterized a novel human gene termed human WAPL that has the characteristics of an oncogene in uterine cervical cancer. WAPL is inducible by human papillomavirus (HPV) E6 and E7 oncoproteins. On the other hand, recent studies have revealed that WAPL regulates sister chromatid resolution by controlling the association of cohesin and chromatin. However, the effects of WAPL overexpression on cervical carcinogenesis are still unclear. Here, we show that WAPL overexpression induces generation of multinucleated cells. In addition, WAPL-overexpressing cells demonstrated increases in chromatid breaks in comparison with control cells. These results were obtained even in HPV-negative cell lines. High frequent premature sister separation by disregulation of cohesin may lead to these results. Thus, our study suggests that unscheduled overexpression of WAPL disturbs mitosis and cytokinesis, and contributes to tumor progression by induction of chromosomal instability (CIN).