Zic2 synergistically enhances Hedgehog signaling pathway through sequestration of Gli1 in the nucleus of cervical cancer cells

Abstract

Cervical cancer is a potentially preventable disease but remains the second most common female malignancy. Human papillomavirus (HPV) is the crucial etiological agent in cervical cancer. However, evidence suggests that HPV infection alone is insufficient to induce malignant changes. Therefore, the transformation from low-grade lesion to invasive cancer must involve other cellular genetic lesions alterating signal transduction pathways. We have recently identified a candidate zinc finger oncogene Zic2 remarkably upregulated and was associated with the Hedgehog (Hh) signaling pathway in cervical cancer cells. Intriguingly, co-immunoprecipitation, subcellular fractionation and immunofluorescent analyses revealed that Zic2 could physically interact and sequester Gli1 in the nucleus which in turn increased Gli-mediated transcriptional activities. This was supported by transient reporter assays that Zic2 significantly increased Gli-promoter luciferase activity in a dose-dependent manner. Functionally, enforced expression of Zic2 in cervical cancer cells resulted in substantial enhancement of cell proliferation rate, anchorage-independent growth ability, and upregulation of the Hh pathway downstream targets. Taken together, these results suggest that Zic2 synergistically enhances the Hh signaling activity through retaining Gli1 in the nucleus of cervical cancer cells.