4.3 Article

FBXW7 and USP7 regulate CCDC6 turnover during the cell cycle and affect cancer drugs susceptibility in NSCLC

期刊

ONCOTARGET
卷 6, 期 14, 页码 12697-12709

出版社

IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3708

关键词

CCDC6; FBXW7; USP7; mitotic kinases; cisplatinum

资金

  1. Associazione Italiana Ricerca sul Cancro (AIRC) [4952]
  2. POR Campania FSE CREME Campania Research In Experimental Medicine
  3. Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR) [PRIN 2009T5NKTB_002]

向作者/读者索取更多资源

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.

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