aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability

Meghan Riddell, Akiko Nakayama, Takao Hikita, Fatemeh Mirzapourshafiyi, Takuji Kawamura, Ayesha Pasha, Mengnan Li, Mikio Masuzawa, Mario Looso, Tim Steinbacher, Klaus Ebnet, Michael Potente, Tomonori Hirose, Shigeo Ohno, Ingrid Fleming, Stefan Gattenlöhner, Phyu P. Aung, Thuy Phung, Osamu Yamasaki, Teruki YanagiHiroshi Umemura, Masanori Nakayama

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Strict regulation of proliferation is vital for development, whereas unregulated cell proliferation is a fundamental characteristic of cancer. The polarity protein atypical protein kinase C lambda/iota (aPKCλ) is associated with cell proliferation through unknown mechanisms. In endothelial cells, suppression of aPKCλ impairs proliferation despite hyperactivated mitogenic signaling. Here we show that aPKCλ phosphorylates the DNA binding domain of forkhead box O1 (FoxO1) transcription factor, a gatekeeper of endothelial growth. Although mitogenic signaling excludes FoxO1 from the nucleus, consequently increasing c-Myc abundance and proliferation, aPKCλ controls c-Myc expression via FoxO1/miR-34c signaling without affecting its localization. We find this pathway is strongly activated in the malignant vascular sarcoma, angiosarcoma, and aPKC inhibition reduces c-Myc expression and proliferation of angiosarcoma cells. Moreover, FoxO1 phosphorylation at Ser218 and aPKC expression correlates with poor patient prognosis. Our findings may provide a potential therapeutic strategy for treatment of malignant cancers, like angiosarcoma.

Original languageEnglish
Article number5357
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Riddell, M., Nakayama, A., Hikita, T., Mirzapourshafiyi, F., Kawamura, T., Pasha, A., Li, M., Masuzawa, M., Looso, M., Steinbacher, T., Ebnet, K., Potente, M., Hirose, T., Ohno, S., Fleming, I., Gattenlöhner, S., Aung, P. P., Phung, T., Yamasaki, O., ... Nakayama, M. (2018). aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability. Nature Communications, 9(1), [5357]. https://doi.org/10.1038/s41467-018-07739-0