Foxo3a drives proliferation in anaplastic thyroid carcinoma through transcriptional regulation of cyclin A1: A paradigm shift that impacts current therapeutic strategies

Laura A. Marlow, Christina A. von Roemeling, Simon J. Cooper, Yilin Zhang, Stephen D. Rohl, Shilpi Arora, Irma M. Gonzales, David O. Azorsa, Honey V. Reddi, Han W. Tun, Heike R. Dö ppler, Peter Storz, Robert C. Smallridge, John A. Copland

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

The Forkhead transcription factor, FoxO3a, is a known suppressor of primary tumor growth through transcriptional regulation of key genes regulating cell cycle arrest and apoptosis. In many types of cancer, in response to growth factor signaling, FoxO3a is phosphorylated by Akt, resulting in its exclusion from the nucleus. Here we show that FoxO3a remains nuclear in anaplastic thyroid carcinoma (ATC). This correlates with lack of Akt phosphorylation at serine473 in ATC cell lines and tissues of ATC patients, providing a potential explanation for nuclear FoxO3a. Mechanistically, nuclear FoxO3a promotes cell cycle progression by transcriptional upregulation of cyclin A1, promoting proliferation of human ATC cells. Silencing FoxO3a with a reverse genetics approach leads to downregulation of CCNA1 mRNA and protein. These combined data suggest an entirely novel function for FoxO3a in ATC promotion by enhancing cell cycle progression and tumor growth through transcriptional upregulation of cyclin A1. This is clinically relevant since we detected highly elevated CCNA1 mRNA and protein levels in tumor tissues of ATC patients. Our data indicate therapeutic inactivation of FoxO3a may lead to attenuation of tumor expansion in ATC. This new paradigm also suggests caution in relation to current dogma focused upon reactivation of FoxO3a as a therapeutic strategy against cancers harboring active PI3-K and Akt signaling pathways.

Original languageEnglish (US)
Pages (from-to)4253-4263
Number of pages11
JournalJournal of cell science
Volume125
Issue number18
DOIs
StatePublished - Dec 1 2012

Keywords

  • Anaplastic thyroid carcinoma
  • Cyclin A1
  • FoxO3a
  • Transcriptional regulation

ASJC Scopus subject areas

  • Cell Biology

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