title: FBXW7 and USP7 regulate CCDC6 turnover during the cell cycle and affect cancer drugs susceptibility in NSCLC.
abstract: CCDC6 gene product is a pro-apoptotic protein substrate of ATM, whose loss or inactivation enhances tumour progression. In primary tumours, the impaired function of CCDC6 protein has been ascribed to CCDC6 rearrangements and to somatic mutations in several neoplasia. Recently, low levels of CCDC6 protein, in NSCLC, have been correlated with tumor prognosis. However, the mechanisms responsible for the variable levels of CCDC6 in primary tumors have not been described yet.We show that CCDC6 turnover is regulated in a cell cycle dependent manner. CCDC6 undergoes a cyclic variation in the phosphorylated status and in protein levels that peak at G2 and decrease in mitosis. The reduced stability of CCDC6 in the M phase is dependent on mitotic kinases and on degron motifs that are present in CCDC6 and direct the recruitment of CCDC6 to the FBXW7 E3 Ubl. The de-ubiquitinase enzyme USP7 appears responsible of the fine tuning of the CCDC6 stability, affecting cells behaviour and drug response.Thus, we propose that the amount of CCDC6 protein in primary tumors, as reported in lung, may depend on the impairment of the CCDC6 turnover due to altered protein-protein interaction and post-translational modifications and may be critical in optimizing personalized therapy.
authors.affiliation: Istituto per l'Endocrinologia e l'Oncologia Sperimentale "Gaetano Salvatore", CNR, Napoli, Italy.|Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Federico II, Napoli, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Morra
authors.affiliation: Istituto per l'Endocrinologia e l'Oncologia Sperimentale "Gaetano Salvatore", CNR, Napoli, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Luise
authors.affiliation: Istituto per l'Endocrinologia e l'Oncologia Sperimentale "Gaetano Salvatore", CNR, Napoli, Italy.|Dipartimento di Scienze Biomediche Avanzate, Università Federico II, Napoli, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Merolla
authors.affiliation: Max Plank Institute, MPI-CBG Dresden, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Poser
authors.affiliation: Istituto per l'Endocrinologia e l'Oncologia Sperimentale "Gaetano Salvatore", CNR, Napoli, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Visconti
authors.affiliation: Dipartimento di Scienze Biomediche Avanzate, Università Federico II, Napoli, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Ilardi
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Federico II, Napoli, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Paladino
authors.affiliation: Harvard Medical School, Beth Israel Deaconess Medical Center, MA, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inuzuka
authors.affiliation: UOC Chirurgia Toracica, Azienda Ospedaliera di Rilievo Nazionale "A.Cardarelli", Napoli, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Guggino
authors.affiliation: UOC Anatomia Patologica, Azienda Ospedaliera di Rilievo Nazionale "A.Cardarelli", Napoli, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Monaco
authors.affiliation: Istituto Toscano Tumori, Core Research Laboratory, Siena, Italy.
authors.forename: David
authors.initials: D
authors.lastname: Colecchia
authors.affiliation: UOC Chirurgia Toracica, Azienda Ospedaliera di Rilievo Nazionale "A.Cardarelli", Napoli, Italy.
authors.forename: Guglielmo
authors.initials: G
authors.lastname: Monaco
authors.affiliation: Istituto per l'Endocrinologia e l'Oncologia Sperimentale "Gaetano Salvatore", CNR, Napoli, Italy.
authors.forename: Aniello
authors.initials: A
authors.lastname: Cerrato
authors.affiliation: Istituto Toscano Tumori, Core Research Laboratory, Siena, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Chiariello
authors.affiliation: Department of Pathology, Joan C. Edwards Cancer Center, Huntington, WV, USA.
authors.forename: Krista
authors.initials: K
authors.lastname: Denning
authors.affiliation: Department of Biochemistry and Microbiology & Department of Surgery, Marshall University, Joan C. Edwards Cancer Center, Huntington, WV, USA.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Claudio
authors.affiliation: Dipartimento di Scienze Biomediche Avanzate, Università Federico II, Napoli, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Staibano
authors.affiliation: Istituto per l'Endocrinologia e l'Oncologia Sperimentale "Gaetano Salvatore", CNR, Napoli, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Celetti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D044783:F-Box Proteins / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D005455:Fluorescent Antibody Technique; D055786:Gene Knockout Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D046888:Tissue Array Analysis; D014162:Transfection; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000076084:Ubiquitin-Specific Peptidase 7
chemical_list: C088832:CCDC6 protein, human; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D034741:RNA, Small Interfering; D044767:Ubiquitin-Protein Ligases; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7
keywords: CCDC6; FBXW7; USP7; cisplatinum; mitotic kinases