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.
Bibliographical noteFunding Information:
We thank the University of Colorado Denver (UCD) Skin Cancer Repository (Carol Amato) for providing human tumors, UCCC Grant (P30CA046934), SDRC Grant (P30AR057212) for helping with FACS sorting and histology, ALM Core (supported by CCTSI Grant UL1TR001082) for helping imaging experiments. We also thank Ms. Angelina Baroffio (Dermatology, UCD) for technical assistance, Dr. Natalie Ahn (Chemistry and Biochemistry, UCB) for helpful comments, and Ms. Joanne Domenico (Dermatology, UCD) for editing the manuscript. This work was supported by an NIH/NCI R01CA197919 (to M. Fujita), Veterans Affairs Merit Review Award 5I01BX001228 (to M. Fujita), Cancer League of Colorado (to M. Fujita), and Tadamitsu Cancer Research Fund (to M. Fujita).
© 2018 American Association for Cancer Research.
ASJC Scopus subject areas
- Cancer Research