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Article: Sirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth
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TitleSirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth
 
AuthorsChen, J2 3
Zhang, B2
Wong, N2
Lo, AWI2
To, KF2
Chan, AWH2
Ng, MHL2
Ho, CYS2
Cheng, SH2
Lai, PBS2
Yu, J2
Ng, HK2
Ling, MT1
Huang, AL3
Cai, XF3
Ko, BCB2
 
Issue Date2011
 
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
 
CitationCancer Research, 2011, v. 71 n. 12, p. 4138-4149 [How to Cite?]
DOI: http://dx.doi.org/10.1158/0008-5472.CAN-10-4274
 
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.
 
ISSN0008-5472
2013 Impact Factor: 9.284
2013 SCImago Journal Rankings: 5.627
 
DOIhttp://dx.doi.org/10.1158/0008-5472.CAN-10-4274
 
ISI Accession Number IDWOS:000291637100010
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).

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorChen, J
 
dc.contributor.authorZhang, B
 
dc.contributor.authorWong, N
 
dc.contributor.authorLo, AWI
 
dc.contributor.authorTo, KF
 
dc.contributor.authorChan, AWH
 
dc.contributor.authorNg, MHL
 
dc.contributor.authorHo, CYS
 
dc.contributor.authorCheng, SH
 
dc.contributor.authorLai, PBS
 
dc.contributor.authorYu, J
 
dc.contributor.authorNg, HK
 
dc.contributor.authorLing, MT
 
dc.contributor.authorHuang, AL
 
dc.contributor.authorCai, XF
 
dc.contributor.authorKo, BCB
 
dc.date.accessioned2012-06-26T05:58:15Z
 
dc.date.available2012-06-26T05:58:15Z
 
dc.date.issued2011
 
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.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationCancer Research, 2011, v. 71 n. 12, p. 4138-4149 [How to Cite?]
DOI: http://dx.doi.org/10.1158/0008-5472.CAN-10-4274
 
dc.identifier.citeulike9589274
 
dc.identifier.doihttp://dx.doi.org/10.1158/0008-5472.CAN-10-4274
 
dc.identifier.epage4149
 
dc.identifier.isiWOS:000291637100010
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).

 
dc.identifier.issn0008-5472
2013 Impact Factor: 9.284
2013 SCImago Journal Rankings: 5.627
 
dc.identifier.issue12
 
dc.identifier.pmid21527554
 
dc.identifier.scopuseid_2-s2.0-79958787784
 
dc.identifier.spage4138
 
dc.identifier.urihttp://hdl.handle.net/10722/149765
 
dc.identifier.volume71
 
dc.languageeng
 
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
 
dc.publisher.placeUnited States
 
dc.relation.ispartofCancer Research
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshApoptosis
 
dc.subject.meshCarcinoma, Hepatocellular - Genetics - Pathology
 
dc.subject.meshCell Aging
 
dc.subject.meshCell Line, Tumor
 
dc.subject.meshCell Proliferation
 
dc.subject.meshDoxorubicin - Pharmacology
 
dc.subject.meshGene Expression Regulation, Neoplastic
 
dc.subject.meshHumans
 
dc.subject.meshImmunohistochemistry
 
dc.subject.meshLiver Neoplasms - Genetics - Pathology
 
dc.subject.meshSirtuin 1 - Analysis - Physiology
 
dc.subject.meshTelomerase - Analysis - Physiology
 
dc.subject.meshTelomere
 
dc.subject.meshTelomere-Binding Proteins - Analysis - Physiology
 
dc.subject.meshTumor Suppressor Protein P53 - Physiology
 
dc.subject.meshUp-Regulation
 
dc.titleSirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth
 
dc.typeArticle
 
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<contributor.author>To, KF</contributor.author>
<contributor.author>Chan, AWH</contributor.author>
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<contributor.author>Ho, CYS</contributor.author>
<contributor.author>Cheng, SH</contributor.author>
<contributor.author>Lai, PBS</contributor.author>
<contributor.author>Yu, J</contributor.author>
<contributor.author>Ng, HK</contributor.author>
<contributor.author>Ling, MT</contributor.author>
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<description.abstract>Hepatocellular 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. &#169;2011 AACR.</description.abstract>
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Author Affiliations
  1. Institute of Health and Biomedical Innovation
  2. Chinese University of Hong Kong
  3. Chongqing University of Medical Sciences