Abstract 1925: CK2 phosphorylates and inhibits tumor suppressor TAp73 function to promote cancer stem cell gene expression and phenotype in head and neck cancer

Abstract

Abstract Cancer development, cell survival, and therapeutic resistance have recently been linked to a small sub-population of cells expressing stem cell genes, and capable of reproducing the cancer cell population, called cancer stem cells (CSC). CK2 (formerly casein kinase II) has emerged as a key signal serine/threonine kinase that modulates diverse signal cascades that regulate cell fate and growth. We previously showed that CK2 is aberrantly expressed and activated in head and neck squamous cell carcinomas (HNSCC). Concomitant inactivation of tumor suppressor TAp73, along with mutation of related family member TP53, is also often observed, but the relationship between CK2, TAp73 inactivation, and CSC is unknown. Here, we observed that classical stem cell genes NANOG, SOX2, and OCT4, are overexpressed in HNSCC with inactivated TAp73 and mtTP53. Inhibition of CK2 by pharmacologic inhibitors or siRNA increased TAp73 mRNA and protein expression, while inhibiting CSC gene expression and the SP. Conversely, knockdown of TAp73 increased CSC gene expression and the SP. Bioinformatic analysis identified a single predicted CK2 threonine phosphorylation site (T27) within the N-terminal transactivation domain of TAp73. Nuclear CK2 and TAp73 interaction, confirmed by co-immunoprecipitation, was attenuated by CK2 inhibitor, or a T27A point-mutation of the predicted CK2 threonine phospho-acceptor site of TAp73. Furthermore, T27A mutation attenuated TAp73 phosphorylation, while enhancing its function in repressing CSC gene expression, and SP cells. Novel CK2 inhibitor CX-4945 inhibited CSC related SP cells, clonogenic survival, and spheroid formation, identifying CK2 modulation of tumor suppressor TAp73 as a potential target for inhibition of CSCs. Our study reveals a novel regulatory mechanism whereby aberrant CK2-mediated inactivation of TAp73 tumor suppressor function promotes key CSC genes and phenotype. Supported by NIDCD intramural project ZIA-DC-00073 Citation Format: Hai Lu, Carol H. Yan, Yansong Bian, Zhong Chen, Carter Van Waes. CK2 phosphorylates and inhibits tumor suppressor TAp73 function to promote cancer stem cell gene expression and phenotype in head and neck cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1925. doi:10.1158/1538-7445.AM2014-1925