title: SIRT2 inhibits non-small cell lung cancer cell growth through impairing Skp2-mediated p27 degradation.
abstract: Skp2 is a component of the E3 ubiquitin ligase which promotes the ubiquitination-associated degradation of a cyclin-dependent kinase inhibitor, p27, resulting in increases in non-small cell lung cancer (NSCLC) cell growth. We recently showed that down-regulation of Sirtuin deacetylases 2 (SIRT2) in NSCLC increased cancer cell growth through suppressing p27. However, the underlying mechanisms remain unknown. Here, we examined the relationship between SIRT2 and Skp2 in regulation of NSCLC cell growth through p27. We found that the levels of SIRT2 significantly decreased, while the levels of Skp2 significantly increased in NSCLC specimens, compared to the paired non-tumor lung tissue. The levels of SIRT2 and Skp2 inversely correlated. Low SIRT2 levels were associated with poor patients' survival. Moreover, in several lung cancer cell lines, the SIRT2 levels significantly decreased and the Skp2 levels significantly increased. Overexpression of SIRT2 promoted Skp2 deacetylation and degradation, resulting in increases in p27 and suppression of NSCLC cell growth, whereas knockdown of Skp2 inhibited Skp2 deacetylation and degradation, resulting in decreases in p27 and increases in NSCLC cell growth. The deacetylation of Skp2 by SIRT2 and degradation of p27 by Skp2 were significantly inhibited by histone deacetylase inhibitor and proteasome inhibitor, respectively. Finally, SIRT2 and Skp2 co-immunoprecipitated in NSCLC cells. Together, our data suggest that SIRT2 may induce Skp2 deacetylation and subsequent degradation to abolish the effects of Skp2 on p27 to affect NSCLC cell growth. Thus, re-expression of SIRT2 may be a promising strategy for treating NSCLC.
authors.affiliation: Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China.
authors.forename: Ziming
authors.initials: Z
authors.lastname: Li
authors.affiliation: Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China.
authors.forename: Jia
authors.initials: J
authors.lastname: Huang
authors.affiliation: Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China.
authors.forename: Qingquan
authors.initials: Q
authors.lastname: Luo
authors.affiliation: Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China.
authors.forename: Shun
authors.initials: S
authors.lastname: Lu
mesh_terms: D000215:Acylation; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D056565:Sirtuin 2 / Q000378:metabolism*; D016019:Survival Analysis; D014162:Transfection
chemical_list: C436291:CDKN1B protein, human; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C474199:SIRT2 protein, human; D056565:Sirtuin 2
keywords: acetylation; cell cycle; lung cancer