title: Antitumor effect of SIRT1 inhibition in human HCC tumor models in vitro and in vivo.
abstract: Sirtuins (SIRT1-7) are a highly conserved family of NAD(+)-dependent enzymes that control the activity of histone and nonhistone regulatory proteins. SIRT1 is purposed to promote longevity and to suppress the initiation of some cancers. Nevertheless, SIRT1 is reported to function as a tumor suppressor as well as an oncogenic protein. Our data show that compared with normal liver or surrounding tumor tissue, SIRT1 is strongly overexpressed in human hepatocellular carcinoma (HCC). In addition, human HCC cell lines (Hep3B, HepG2, HuH7, HLE, HLF, HepKK1, skHep1) were screened for the expression of the sirtuin family members and only SIRT1 was consistently overexpressed compared with normal hepatocytes. To determine its effect on HCC growth, SIRT1 activity was inhibited either with lentiviruses expressing short hairpin RNAs or with the small molecule inhibitor, cambinol. Knockdown or inhibition of SIRT1 activity had a cytostatic effect, characterized by an altered morphology, impaired proliferation, an increased expression of differentiation markers, and cellular senescence. In an orthotopic xenograft model, knockdown of SIRT1 resulted in 50% fewer animals developing tumors and cambinol treatment resulted in an overall lower tumor burden. Taken together, our data show that inhibition of SIRT1 in HCC cells impairs their proliferation in vitro and tumor formation in vivo. These data suggest that SIRT1 expression positively influences the growth of HCC and support further studies aimed to block its activity alone or in combination as a novel treatment strategy.
authors: Clinic of Visceral Surgery and Medicine, Department of Clinical Research, University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland.
authors: Simone
authors: S
authors: Portmann
authors: René
authors: R
authors: Fahrner
authors: Antje
authors: A
authors: Lechleiter
authors: Adrian
authors: A
authors: Keogh
authors: Sarah
authors: S
authors: Overney
authors: Alexander
authors: A
authors: Laemmle
authors: Kei
authors: K
authors: Mikami
authors: Matteo
authors: M
authors: Montani
authors: Mario P
authors: MP
authors: Tschan
authors: Daniel
authors: D
authors: Candinas
authors: Deborah
authors: D
authors: Stroka
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D009281:Naphthalenes; D011744:Pyrimidinones; C510718:cambinol; D056564:Sirtuin 1