File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Sirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth

TitleSirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth
Authors
Issue Date2011
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
Cancer Research, 2011, v. 71 n. 12, p. 4138-4149 How to Cite?
AbstractHepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. Treatment of HCC is complicated by the fact that the disease is often diagnosed at an advanced stage when it is no longer amenable to curative surgery, and current systemic chemotherapeutics are mostly inefficacious. Sirtuin 1 (SIRT1) is a class III histone deacetylase that is implicated in gene regulations and stress resistance. In this study, we found that SIRT1 is essential for the tumorigenesis of HCC. We showed that although SIRT1 was expressed at very low levels in normal livers, it was overexpressed in HCC cell lines and in a subset of HCC. Tissue microarray analysis of HCC and adjacent nontumoral liver tissues revealed a positive correlation between the expression levels of SIRT1 and advancement in tumor grades. Downregulation of SIRT1 consistently suppressed the proliferation of HCC cells via the induction of cellular senescence or apoptosis. SIRT1 silencing also caused telomere dysfunction-induced foci and nuclear abnormality that were clearly associated with reduced expressions of telomerase reverse transcriptase (TERT), and PTOP, which is a member of the shelterin complex. Ectopic expression of either TERT or PTOP in SIRT1-depleted cells significantly restored cell proliferation. There was also a positive correlation between the level of induction of SIRT1 and PTOP in human HCC. Finally, SIRT1-silencing sensitized HCC cells to doxorubicin treatment. Together, our findings reveal a novel function for SIRT1 in telomere maintenance of HCC, and they rationalize the clinical exploration of SIRT1 inhibitors for HCC therapy. ©2011 AACR.
Persistent Identifierhttp://hdl.handle.net/10722/149765
ISSN
2014 Impact Factor: 9.329
2013 SCImago Journal Rankings: 5.627
ISI Accession Number ID
Funding AgencyGrant Number
Research Grant CouncilCUHK 466108
467210
HKRGCCUHK 4712/07M
Funding Information:

This work is supported by the Research Grant Council Grants CUHK 466108 and 467210 to B.C.B. Ko. Laboratory of A.W.I. Lo is supported by HKRGC (CUHK 4712/07M).

References

 

DC FieldValueLanguage
dc.contributor.authorChen, Jen_US
dc.contributor.authorZhang, Ben_US
dc.contributor.authorWong, Nen_US
dc.contributor.authorLo, AWIen_US
dc.contributor.authorTo, KFen_US
dc.contributor.authorChan, AWHen_US
dc.contributor.authorNg, MHLen_US
dc.contributor.authorHo, CYSen_US
dc.contributor.authorCheng, SHen_US
dc.contributor.authorLai, PBSen_US
dc.contributor.authorYu, Jen_US
dc.contributor.authorNg, HKen_US
dc.contributor.authorLing, MTen_US
dc.contributor.authorHuang, ALen_US
dc.contributor.authorCai, XFen_US
dc.contributor.authorKo, BCBen_US
dc.date.accessioned2012-06-26T05:58:15Z-
dc.date.available2012-06-26T05:58:15Z-
dc.date.issued2011en_US
dc.identifier.citationCancer Research, 2011, v. 71 n. 12, p. 4138-4149en_US
dc.identifier.issn0008-5472en_US
dc.identifier.urihttp://hdl.handle.net/10722/149765-
dc.description.abstractHepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. Treatment of HCC is complicated by the fact that the disease is often diagnosed at an advanced stage when it is no longer amenable to curative surgery, and current systemic chemotherapeutics are mostly inefficacious. Sirtuin 1 (SIRT1) is a class III histone deacetylase that is implicated in gene regulations and stress resistance. In this study, we found that SIRT1 is essential for the tumorigenesis of HCC. We showed that although SIRT1 was expressed at very low levels in normal livers, it was overexpressed in HCC cell lines and in a subset of HCC. Tissue microarray analysis of HCC and adjacent nontumoral liver tissues revealed a positive correlation between the expression levels of SIRT1 and advancement in tumor grades. Downregulation of SIRT1 consistently suppressed the proliferation of HCC cells via the induction of cellular senescence or apoptosis. SIRT1 silencing also caused telomere dysfunction-induced foci and nuclear abnormality that were clearly associated with reduced expressions of telomerase reverse transcriptase (TERT), and PTOP, which is a member of the shelterin complex. Ectopic expression of either TERT or PTOP in SIRT1-depleted cells significantly restored cell proliferation. There was also a positive correlation between the level of induction of SIRT1 and PTOP in human HCC. Finally, SIRT1-silencing sensitized HCC cells to doxorubicin treatment. Together, our findings reveal a novel function for SIRT1 in telomere maintenance of HCC, and they rationalize the clinical exploration of SIRT1 inhibitors for HCC therapy. ©2011 AACR.en_US
dc.languageengen_US
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/en_US
dc.relation.ispartofCancer Researchen_US
dc.subject.meshApoptosisen_US
dc.subject.meshCarcinoma, Hepatocellular - Genetics - Pathologyen_US
dc.subject.meshCell Agingen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshCell Proliferationen_US
dc.subject.meshDoxorubicin - Pharmacologyen_US
dc.subject.meshGene Expression Regulation, Neoplasticen_US
dc.subject.meshHumansen_US
dc.subject.meshImmunohistochemistryen_US
dc.subject.meshLiver Neoplasms - Genetics - Pathologyen_US
dc.subject.meshSirtuin 1 - Analysis - Physiologyen_US
dc.subject.meshTelomerase - Analysis - Physiologyen_US
dc.subject.meshTelomereen_US
dc.subject.meshTelomere-Binding Proteins - Analysis - Physiologyen_US
dc.subject.meshTumor Suppressor Protein P53 - Physiologyen_US
dc.subject.meshUp-Regulationen_US
dc.titleSirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growthen_US
dc.typeArticleen_US
dc.identifier.emailLing, MT:patling@hkucc.hku.hken_US
dc.identifier.authorityLing, MT=rp00449en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1158/0008-5472.CAN-10-4274en_US
dc.identifier.pmid21527554en_US
dc.identifier.scopuseid_2-s2.0-79958787784en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79958787784&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume71en_US
dc.identifier.issue12en_US
dc.identifier.spage4138en_US
dc.identifier.epage4149en_US
dc.identifier.isiWOS:000291637100010-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridChen, J=49461011000en_US
dc.identifier.scopusauthoridZhang, B=49462034000en_US
dc.identifier.scopusauthoridWong, N=7202836653en_US
dc.identifier.scopusauthoridLo, AWI=7102780722en_US
dc.identifier.scopusauthoridTo, KF=36785812800en_US
dc.identifier.scopusauthoridChan, AWH=49460994500en_US
dc.identifier.scopusauthoridNg, MHL=35292609300en_US
dc.identifier.scopusauthoridHo, CYS=13404519800en_US
dc.identifier.scopusauthoridCheng, SH=7404681588en_US
dc.identifier.scopusauthoridLai, PBS=7202946421en_US
dc.identifier.scopusauthoridYu, J=35351306800en_US
dc.identifier.scopusauthoridNg, HK=7401619354en_US
dc.identifier.scopusauthoridLing, MT=7102229780en_US
dc.identifier.scopusauthoridHuang, AL=7402307198en_US
dc.identifier.scopusauthoridCai, XF=49460958900en_US
dc.identifier.scopusauthoridKo, BCB=7102833927en_US
dc.identifier.citeulike9589274-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats