title: NEDD4 is overexpressed in colorectal cancer and promotes colonic cell growth independently of the PI3K/PTEN/AKT pathway.
abstract: Ubiquitination controls multiple cellular processes relevant to cancer pathogenesis. Using Gene Set Enrichment Analysis of an mRNA transcriptome dataset, we have identified genes encoding components of the ubiquitin system that are differentially expressed in colorectal cancers as compared to normal colonic mucosa. Among the significantly overexpressed genes was NEDD4 (neural precursor cell-expressed developmentally down-regulated 4), the prototype member of the HECT (homologous to E6AP C-terminus) E3 ubiquitin ligase family. Previous studies have shown that NEDD4 may act as an oncoprotein by inducing ubiquitination and degradation of the tumor suppressor protein PTEN (phosphatase and tensin homolog). To investigate its functional importance in colorectal cancer, HCT-15 and LoVo colon cancer cells were depleted of NEDD4 by small interfering RNA. The depletion resulted in reduced growth and altered cell morphology in both cell lines. However, NEDD4 depletion did not affect the PTEN protein level or PI3K/AKT signaling pathway activation. Moreover, ectopic expression of NEDD4 did not influence the PTEN subcellular localization or protein level. Collectively, these data demonstrate that NEDD4 is overexpressed in colorectal cancers, and suggest that NEDD4 promotes growth of colon cancer cells independently of PTEN and PI3K/AKT signaling.
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Eide
authors.forename: Lina
authors.initials: L
authors.lastname: Cekaite
authors.forename: Stine A
authors.initials: SA
authors.lastname: Danielsen
authors.forename: Ina A
authors.initials: IA
authors.lastname: Eilertsen
authors.forename: Ane
authors.initials: A
authors.lastname: Kjenseth
authors.forename: Tone A
authors.initials: TA
authors.lastname: Fykerud
authors.forename: Trude H
authors.initials: TH
authors.lastname: Ågesen
authors.forename: Jarle
authors.initials: J
authors.lastname: Bruun
authors.forename: Edgar
authors.initials: E
authors.lastname: Rivedal
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Lothe
authors.forename: Edward
authors.initials: E
authors.lastname: Leithe
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D056827:Endosomal Sorting Complexes Required for Transport / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000075702:Nedd4 Ubiquitin Protein Ligases; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D025341:Principal Component Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase