GOLPH3 modulates mTOR signalling and rapamycin sensitivity in cancer.
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.
Scott
Kenneth L
KL
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Kabbarah
Omar
O
Liang
Mei-Chih
MC
Ivanova
Elena
E
Anagnostou
Valsamo
V
Wu
Joyce
J
Dhakal
Sabin
S
Wu
Min
M
Chen
Shujuan
S
Feinberg
Tamar
T
Huang
Joseph
J
Saci
Abdel
A
Widlund
Hans R
HR
Fisher
David E
DE
Xiao
Yonghong
Y
Rimm
David L
DL
Protopopov
Alexei
A
Wong
Kwok-Kin
KK
Chin
Lynda
L
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000503:physiopathology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics
D000903:Antibiotics, Antineoplastic; D004268:DNA-Binding Proteins; C429024:GOLPH3 protein, human; D008565:Membrane Proteins; C509201:SUB1 protein, human; D014157:Transcription Factors; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus