The PRKCI and SOX2 Oncogenes Are Coamplified and Cooperate to Activate Hedgehog Signaling in Lung Squamous Cell Carcinoma
Menée in vitro, in vivo et à partir de données du projet "The Cancer Genome Atlas", cette étude met en évidence des mécanismes par lesquels deux protéines, PRKCI et SOX2, coopèrent pour activer la signalisation Hedgehog dans les carcinomes épidermoïdes du poumon
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 C¹ (PKC¹) 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. PKC¹-mediated SOX2 phosphorylation is required for HHAT promoter occupancy, HHAT expression, and maintenance of a stem-like phenotype. Primary LSCC tumors coordinately overexpress PKC¹, SOX2, and HHAT and require PKC¹-SOX2-HHAT signaling to maintain a stem-like phenotype. Thus, PKC¹ and SOX2 are genetically, biochemically, and functionally linked in LSCC, and together they drive tumorigenesis by establishing a cell-autonomous Hh signaling axis. "PRKCI and SOX2 are coamplified and coordinately overexpressed in LSCC tumors "PKC¹ transcriptionally regulates expression of Hedgehog acyltransferase (HHAT) "PKC¹ directly phosphorylates and recruits SOX2 to the HHAT promoter"PKC¹ and SOX2 activate autocrine Hh signaling to maintain LSCC stem-like cells Justilien et al. find a functional link between proteins encoded by PRKCI and SOX2 that are often coamplified in lung squamous cell carcinoma. PKC¹ phosphorylates SOX2, enabling it to increase HHAT expression that, in turn, activates cell-autonomous Hedgehog signaling to sustain a stem-like phenotype.