Genome-wide copy number analyses of human cancers identified a frequent 5p13 amplification in several solid tumour types, including lung (56%), ovarian (38%), breast (32%), prostate (37%) and melanoma (32%). Here, using integrative analysis of a genomic profile of the region, we identify a Golgi protein, GOLPH3, as a candidate targeted for amplification. Gain- and loss-of-function studies in vitro and in vivo validated GOLPH3 as a potent oncogene. Physically, GOLPH3 localizes to the trans-Golgi network and interacts with components of the retromer complex, which in yeast has been linked to target of rapamycin (TOR) signalling. Mechanistically, GOLPH3 regulates cell size, enhances growth-factor-induced mTOR (also known as FRAP1) signalling in human cancer cells, and alters the response to an mTOR inhibitor in vivo. Thus, genomic and genetic, biological, functional and biochemical data in yeast and humans establishes GOLPH3 as a new oncogene that is commonly targeted for amplification in human cancer, and is capable of modulating the response to rapamycin, a cancer drug in clinical use.
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We thank R. DePinho for critical reading of the manuscript, and L. Cantley, as well as members of the Chin laboratory, for helpful discussion. We thank H. Ying for assistance with confocal microscopy. The rabbit polyclonal antibody against human GOLPH3 was kindly provided by J. J. Bergeron of McGill University. Mouse monoclonal antibody against human GOLPH3, C19, was generated at the Dana-Farber/Harvard Cancer Center Monoclonal Antibody Core Facility. K.L.S. is at present supported by a Postdoctoral Fellowship from the American Cancer Society (PF-07-039-01-CSM), and K.L.S. and O.K. were previously supported by a National Institutes of Health (NIH) Training Grant appointment in the Department of Dermatology at Brigham and Women’s Hospital (5-T32-AR07098-31). K.-K.W. was supported by a Program of Research Excellence (SPORE) grant (P50 CA090578) and NIH grants (R01 AG2400401; R01 CA122794). The AQUA immunofluorescence study was supported by a grant from the NIH to D.L.R. (RO-1 CA 114277). This work is primarily supported by grants from the NIH to L.C. (RO1 CA93947; P50 CA93683).
Author Contribution O.K. identified GOLPH3 as an oncogene target of 5p13; K.L.S. performed oncogene validation and mechanistic studies; E.I. and A.P. performed TMA FISH analysis; H.R.W. and D.E.F. performed the HMEL anchorage-independent growth assay; S.D. and J.W. assisted with immunofluorescence assays and provided technical support; M.W. performed the co-immunoprecipitation assays; V.A. and D.L.R. performed AQUA analysis; S.C. assisted with cell culture studies; A.S. aided phospholipid and biochemical analyses; M.-C.L. and K.-K.W. performed rapamycin xenograft assays; Y.X. performed computational analyses; T.F. and J.H. provided technical support; L.C. supervised the experiments and data interpretation; K.L.S. and L.C. wrote the manuscript.
This file contains Supplementary Tables 1-4 and Supplementary Figures S1-S5 with Legends.