CDK1 Interacts with Sox2 and Promotes Tumor Initiation in Human Melanoma

Abstract

Cancers are comprised 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 pharmacological 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 CDK1-hi tumor cells identified a pathway signature common in all three cancer types, including E2F, G2M, MYC, and spermatogenesis, confirming a stem-like nature of CDK1-hi 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.

ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL

“…For instance, SOX2 has been shown to contribute to melanoma metastasis 35 and to be highly expressed in melanomas compared to nevi 36 . In addition, SOX2 regulates survival, self-renewal, and tumorigenicity of human melanoma-initiating cells 11 , 37 and participates in dormancy regulation of melanoma tumor-repopulating cells 38 . SOX2 has been recently related to the acquisition of an aggressive oxidative tumor phenotype endowed with enhanced drug resistance and metastatic ability 39 .…”

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

“…Similarly as previously shown [73], vemurafenib resistance was developed independently from SOX2 expression in drug-naïve cells, however, while in the study of Cesarini et al, SOX2 was strongly upregulated only in one out of three vemurafenib-resistant cell lines, in our study SOX2 upregulation was observed in all six PLXR cell lines. As several reports suggest genetic context-dependent role of SOX2 in melanoma [73][74][75][76][77], regulation of SOX2 expression and the role of this transcription factor in resistant melanoma cells remain to be clarified.…”

Interleukin‐37 is highly expressed in regulatory T cells of melanoma patients and enhanced by melanoma cell secretome

“…MCM was obtained from supernatants of human metastatic melanoma cells, 1205Lu (obtained from Rockland Immunochemicals, Inc, Limerick, PA), after 24 hours of cultivation in Opti‐MEM I Reduced Serum Media (Life Technologies, Grand Island, NY), and centrifuged at 210 g for 5 minutes . 1205Lu cells were routinely checked for mycoplasma by PCR as previously described, and authenticated using short tandem repeat (STR) analysis by Barbara Davis Center Bioresource Core. To treat PBMCs with MCM or IL‐1β, cells were cultured for 24 hours with complete media containing 10% MCM, 50% MCM, or 10 ng/mL IL‐1β (Life Technologies, Thermo Fisher).…”