TY - JOUR
T1 - The PRKCI and SOX2 Oncogenes Are Coamplified and Cooperate to Activate Hedgehog Signaling in Lung Squamous Cell Carcinoma
AU - Justilien, Verline
AU - Walsh, Michael P.
AU - Ali, Syed A.
AU - Thompson, E. Aubrey
AU - Murray, Nicole R.
AU - Fields, Alan P.
N1 - Funding Information:
We thank Dr. Robert Bergen and Benjamin Madden of the Mayo Clinic Proteomics Research Center for performing MS analysis of SOX2 phosphorylation, Dr. John Odell for consenting individuals and obtaining fresh primary lung tumor tissue, Dr. Al Copland for the retroviral firefly luciferase construct, Ms. Capella Weems and Dr. Lee Jamieson for technical assistance, Ms. Brandy Edenfield for immunohistochemical analysis, the Mayo Clinic Florida Biospecimen Acquisition and Processing laboratory for procurement of primary lung tumor tissues, and the Mayo Clinic Advanced Genomic Technology Center for RNA-seq and data analysis. We also acknowledge Dr. Howard Crawford and members of the Fields laboratory for critical feedback on the manuscript, and Kevin M. Youel for artwork in the graphical abstract. This work was supported by grants from National Institutes of Health/National Cancer Institute (R01 CA081436-16 and R21 CA151250-02), the V Foundation for Cancer Research, the James and Esther King Biomedical Research Program (1KG-05-33971), and the Mayo Clinic Center for Individualized Medicine to A.P.F.; and a National Institutes of Health Research Supplement to Promote Diversity in Health-Related Research Award from the National Cancer Institute to V.J. A.P.F. is the Monica Flynn Jacoby Professor of Cancer Research, an endowment fund that provides partial support for the investigator’s research program.
PY - 2014/2/10
Y1 - 2014/2/10
N2 - We report that two oncogenes coamplified on chromosome 3q26, PRKCI and SOX2, cooperate to drive a stem-like phenotype in lung squamous cell carcinoma (LSCC). Protein kinase Cι (PKCι) phosphorylates SOX2, a master transcriptional regulator of stemness, and recruits it to the promoter of Hedgehog (Hh) acyltransferase (HHAT) that catalyzes the rate-limiting step in Hh ligand production. PKCι-mediated SOX2 phosphorylation is required for HHAT promoter occupancy, HHAT expression, and maintenance of a stem-like phenotype. Primary LSCC tumors coordinately overexpress PKCι, SOX2, and HHAT and require PKCι-SOX2-HHAT signaling to maintain a stem-like phenotype. Thus, PKCι and SOX2 are genetically, biochemically, and functionally linked in LSCC, and together they drive tumorigenesis by establishing a cell-autonomous Hh signaling axis.
AB - We report that two oncogenes coamplified on chromosome 3q26, PRKCI and SOX2, cooperate to drive a stem-like phenotype in lung squamous cell carcinoma (LSCC). Protein kinase Cι (PKCι) phosphorylates SOX2, a master transcriptional regulator of stemness, and recruits it to the promoter of Hedgehog (Hh) acyltransferase (HHAT) that catalyzes the rate-limiting step in Hh ligand production. PKCι-mediated SOX2 phosphorylation is required for HHAT promoter occupancy, HHAT expression, and maintenance of a stem-like phenotype. Primary LSCC tumors coordinately overexpress PKCι, SOX2, and HHAT and require PKCι-SOX2-HHAT signaling to maintain a stem-like phenotype. Thus, PKCι and SOX2 are genetically, biochemically, and functionally linked in LSCC, and together they drive tumorigenesis by establishing a cell-autonomous Hh signaling axis.
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U2 - 10.1016/j.ccr.2014.01.008
DO - 10.1016/j.ccr.2014.01.008
M3 - Article
C2 - 24525231
AN - SCOPUS:84893539239
SN - 1535-6108
VL - 25
SP - 139
EP - 151
JO - Cancer cell
JF - Cancer cell
IS - 2
ER -