CDK1 interacts with SOX2 and promotes tumor initiation in human melanoma

Dinoop Ravindran Menon, Yuchun Luo, John J. Arcaroli, Sucai Liu, Lekha Nair KrishnanKutty, Douglas G. Osborne, Yang Li, Jenny Mae Samson, Stacey Bagby, Aik-Choon Tan, William A. Robinson, Wells A. Messersmith, Mayumi Fujita

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17 Citations (Scopus)

Abstract

Cancers are composed of heterogeneous subpopulations with various tumor-initiating capacities, yet key stem cell genes associated with enhanced tumor-initiating capacities and their regulatory mechanisms remain elusive. Here, we analyzed patient-derived xenografts from melanoma, colon, and pancreatic cancer tissues and identified enrichment of tumor-initiating cells in MHC class I-hi cells, where CDK1, a master regulator of the cell cycle, was upregulated. Overexpression of CDK1, but not its kinase-dead variant, in melanoma cells increased their spheroid forming ability, tumorigenic potential, and tumor-initiating capacity; inhibition of CDK1 with pharmacologic agents reduced these characteristics, which was unexplained by the role of CDK1 in regulating the cell cycle. Proteomic analysis revealed an interaction between CDK1 and the pluripotent stem cell transcription factor Sox2. Blockade or knockdown of CDK1 resulted in reduced phosphorylation, nuclear localization, and transcriptional activity of Sox2. Knockout of Sox2 in CDK1-overexpressing cells reduced CDK1-driven tumor-initiating capacity substantially. Furthermore, GSEA analysis of CDK1hi tumor cells identified a pathway signature common in all three cancer types, including E2F, G2M, MYC, and spermatogenesis, confirming a stem-like nature of CDK1hi tumor cells. These findings reveal a previously unrecognized role for CDK1 in regulating tumor-initiating capacity in melanoma and suggest a novel treatment strategy in cancer via interruption of CDK1 function and its protein-protein interactions. Significance: These findings uncover CDK1 as a new regulator of Sox2 during tumor initiation and implicate the CDK1–Sox2 interaction as a potential therapeutic target in cancer.

Original languageEnglish
Pages (from-to)6561-6574
Number of pages14
JournalCancer Research
Volume78
Issue number23
DOIs
Publication statusPublished - 2018 Dec 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Menon, D. R., Luo, Y., Arcaroli, J. J., Liu, S., KrishnanKutty, L. N., Osborne, D. G., Li, Y., Samson, J. M., Bagby, S., Tan, A-C., Robinson, W. A., Messersmith, W. A., & Fujita, M. (2018). CDK1 interacts with SOX2 and promotes tumor initiation in human melanoma. Cancer Research, 78(23), 6561-6574. https://doi.org/10.1158/0008-5472.CAN-18-0330