title: Expression/localization patterns of sirtuins (SIRT1, SIRT2, and SIRT7) during progression of cervical cancer and effects of sirtuin inhibitors on growth of cervical cancer cells.
abstract: Sirtuins belong to the family of class III histone deacetylases; its role in neoplasia is controversial as both tumor-suppressive and promoting functions have been reported. There are very few reports available, where expressions of sirtuin isoforms are comprehensively analyzed during neoplasia. Therefore, in the present study, the expression of SIRT1, SIRT2, and SIRT7 during different stages of cervical cancer progression was analyzed. The normal cervical epithelium showed feeble expression of sirtuin isoforms, SIRT1, SIRT2, and SIRT7. A significant increase in SIRT1 expression was noted in the cytoplasm as well as in the nucleus of proliferative layers of cervical epithelium in squamous intraepithelial lesions (SIL); however, in the squamous cell carcinomas (SCC), a heterogeneous pattern of SIRT1 expression varying from low to high was noted. A progressive increase in the expression of both SIRT2 and SIRT7 was noted during cancer progression in the following order: normal < preneoplasia < cancer. Cervical cancer cell lines, HeLa and SiHa, showed higher levels of SIRT1 and SIRT2 in comparison to the immortalized cell counterpart, HaCaT. Specific inhibitors of SIRT1 (Ex527) and SIRT2 (AGK2) impaired the growth of the cervical cancer cells, SiHa, but not of the HaCaT cells. SIRT1 inhibition caused cell death, while SIRT2 inhibition resulted in cell cycle arrest. In conclusion, we report the overexpression of SIRT2 and SIRT7 proteins in cervical cancer and suggest probable application of sirtuin inhibitors as therapeutic targets. Further, a specific increase in the levels of SIRT1 in intraepithelial lesion makes it a promising candidate for identification of preneoplastic changes.
authors: Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India.
authors: Sapna
authors: S
authors: Singh
authors: P Uday
authors: PU
authors: Kumar
authors: Suresh
authors: S
authors: Thakur
authors: Shashi
authors: S
authors: Kiran
authors: Bijoya
authors: B
authors: Sen
authors: Shreya
authors: S
authors: Sharma
authors: Vishnu Vardhan
authors: VV
authors: Rao
authors: A R
authors: AR
authors: Poongothai
authors: Gayatri
authors: G
authors: Ramakrishna
mesh_terms: D002227:Carbazoles / Q000008:administration & dosage; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D005260:Female; D005663:Furans / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D011804:Quinolines / Q000008:administration & dosage; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; C521855:AGK2 compound; D002227:Carbazoles; D005663:Furans; D011804:Quinolines; C510661:SIRT7 protein, human; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2; D037761:Sirtuins