Zic2 synergistically enhances Hedgehog signalling through nuclear retention of Gli1 in cervical cancer cells

• Published in: The Journal of pathology Vol. 225; no. 4; pp. 525 - 534
• Main Authors: Chan, David W, Liu, Vincent WS, Leung, Ling Yang, Yao, Kwok Ming, Chan, Karen KL, Cheung, Annie NY, Ngan, Hextan YS
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.12.2011; Wiley
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Biological and medical sciences; Cell Line, Transformed; Cell Line, Tumor; Cell Nucleus - metabolism; cervical cancer; Female; Female genital diseases; Gene Expression Regulation, Neoplastic; Gli1; Gynecology. Andrology. Obstetrics; Hedgehog; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Humans; Investigative techniques, diagnostic techniques (general aspects); Medical sciences; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; RNA, Messenger - metabolism; Signal Transduction; Transcription Factors - genetics; Transcription Factors - metabolism; Tumors; tumourigenicity; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology; Zic2; Zinc Finger Protein GLI1; Transcription factor Gli1; Tumorigenicity; Malignant tumor; Retention; Gli1; Female genital diseases; Anatomic pathology; Hedgehog; tumourigenicity; Zic2; Hedgehog protein; Uterine cervix diseases; Cervical cancer; Tumor cell; Cancer
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2901

Aberrant activation of Hedgehog (Hh) signalling has been implicated in the pathogenesis of human cancers. However, the cognate molecular mechanisms contributing to this disregulated pathway are incompletely understood. In this study, we showed that Zic2 was frequently over‐expressed and associated with high‐grade cervical cancer (p = 0.032), high levels of Gli1 (p < 0.001) and CyclinD1 (p < 0.001) by immunohistochemical and quantitative RT–PCR analyses. Further biochemical studies using luciferase reporter, co‐immunoprecipitation, subcellular fractionation and immunofluorescence analyses demonstrated that Zic2 can physically interact with Gli1 and retain it in the nucleus, which in turn increases Gli‐mediated transcriptional activity. Gain‐ and loss‐of‐function analyses of Zic2 showed that Zic2 could increase Hh signalling activity, cell proliferation and anchorage‐independent growth ability in cervical cancer cells. Conversely, deletion of the zinc finger domain at C‐terminus of Zic2 significantly abrogated its interaction with Gli1, the retention of Gli1 in the nucleus, effects on Hh signalling activity and oncogenic properties in cervical cancer cells. Our findings suggest that Zic2 is a positive modulator increasing Gli1 transcriptional and oncogenic activity by retaining Gli1 in the nucleus of cervical cancer cells. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.