A novel nuclear Src and p300 signaling axis controls migratory and invasive behavior in pancreatic cancer
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David Paladino1,2, Peibin Yue1,2, Hideki Furuya3, Jared Acoba3, Charles J. Rosser3, James Turkson1,2
1Natural Products and Experimental Therapeutics Program, University of Hawaii Cancer Center, University of Hawaii, Manoa, Honolulu, HI 96813, USA
2Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii, Manoa, Honolulu, HI 96813, USA
3Clinical and Translational Research Program, University of Hawaii Cancer Center, University of Hawaii, Manoa, Honolulu, HI 96813, USA
James Turkson, e-mail: [email protected]
Keywords: Src, p300, pancreatic cancer, migration, invasion
Received: November 12, 2015 Accepted: November 23, 2015 Published: December 17, 2015
The presence of Src in the nuclear compartment has been previously reported, although its significance has remained largely unknown. We sought to delineate the functions of the nuclear pool of Src within the context of malignant progression. Active Src is localized within the nuclei of human pancreatic cancer cells and mouse fibroblasts over-expressing c-Src where it is associated with p300. Nuclear Src additionally promotes the tyrosine phosphorylation of p300 in pancreatic cancer Panc-1 cells. Src, together with p300, is associated with the high-mobility group AT-hook (HMGA)2 and SET and MYND domain-containing protein (SMYD)3 gene promoters and regulates their expression in a Src-dependent manner. These nuclear Src-dependent events correlate with anchorage-independent soft-agar growth and the migratory properties in both pancreatic Panc-1 cells and mouse fibroblasts over-expressing Src. Moreover, analyses of human pancreatic ductal adenocarcinoma (PDAC) tumor tissues detected the association of nuclear Src with the HMGA2 and SMYD3 gene promoters. Our findings for the first time show the critical importance of nuclear Src and p300 function in the migratory properties of pancreatic cancer cells. Further, data together identify a previously unknown role of nuclear Src in the regulation of gene expression in association with p300 within the context of cells harboring activated or over-expressing Src. This novel mechanism of nuclear Src-p300 axis in PDAC invasiveness and metastasis may provide an opportunity for developing more effective early clinical interventions for this lethal disease.
Active Src is complexed with and phosphorylates p300 in the nucleus, and the complex is bound to HMGA2 and SMYD3 genes, thereby regulating their expression to promote pancreatic tumor cell migration and invasiveness.
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