Abstract
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.
Copyright © 2014 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acyltransferases / antagonists & inhibitors
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Acyltransferases / genetics
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Acyltransferases / metabolism*
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Animals
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Apoptosis
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Blotting, Western
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Carcinoma, Squamous Cell / genetics
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology*
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Cell Proliferation
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / pathology*
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High-Throughput Nucleotide Sequencing
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Humans
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Immunoenzyme Techniques
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / genetics
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Isoenzymes / metabolism*
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology*
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Mice
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Promoter Regions, Genetic / genetics
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / genetics
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Protein Kinase C / metabolism*
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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SOXB1 Transcription Factors / antagonists & inhibitors
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SOXB1 Transcription Factors / genetics
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SOXB1 Transcription Factors / metabolism*
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Signal Transduction
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Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Tumor Cells, Cultured
Substances
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Isoenzymes
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RNA, Messenger
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RNA, Small Interfering
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SOX2 protein, human
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SOXB1 Transcription Factors
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Acyltransferases
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HHAT protein, human
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Protein Kinase C
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protein kinase C lambda