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AP-2 and AP-2 regulate tumor progression via specific genetic programs

Francesca Orso^*,,, Elisa Penna^*,, Daniela Cimino^*,, Elena Astanina^*, Federica Maione^*, Donatella Valdembri^*, Enrico Giraudo^*,, Guido Serini^*,, Piero Sismondi^*, Michele De Bortoli^*, and Daniela Taverna^*,,,1

^* Institute for Cancer Research and Treatment,

Molecular Biotechnology Center, Department of Oncological Sciences, and

Center for Complex Systems in Molecular Biology and Medicine, University of Torino, Torino, Italy

¹Correspondence: Molecular Biotechnology Center, Department of Oncological Sciences, University of Torino, Via Nizza, 52, 10126 Torino, Italy. E-mail: daniela.taverna{at}unito.it

The events occurring during tumor formation and progression display similarities to some of the steps in embryonic morphogenesis. The family of AP-2 proteins consists of five different transcription factors (, β, , , and ) that play relevant roles in embryonic development, as demonstrated by the phenotypes of the corresponding knockout mice. Here, we show that AP-2 and AP-2 proteins play an essential role in tumorigenesis. Down-modulation of AP-2 expression in tumor cells by RNA interference (RNAi) led to enhanced tumor growth and reduced chemotherapy-induced cell death, as well as migration and invasion. Most of these biological modulations were rescued by AP-2 overexpression. We observed that increased xenotransplant growth was mostly due to highly enhanced proliferation of the tumor cells together with reduced innate immune cell recruitment. Moreover, we showed that migration impairment was mediated, at least in part, by secreted factors. To identify the genetic programs involved in tumorigenesis, we performed whole genome microarray analysis of AP-2 knockdown cells and observed that AP-2 regulates specific genes involved in cell cycle, cell death, adhesion, and migration. In particular, we showed that ESDN, EREG, and CXCL2 play a major role in AP-2 controlled migration, as ablation of any of these genes severely altered migration.—Orso, F., Penna, E., Cimino, D., Astanina, E., Maione, F., Valdembri, D., Giraudo, E., Serini, G., Sismondi, P., De Bortoli, M., Taverna, D. AP-2 and AP-2 regulate tumor progression via specific genetic programs.

Key Words: transcription factor • migration • microarray

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