Article: Sirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth
| Title | Sirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth | ||||||
|---|---|---|---|---|---|---|---|
| Authors | Chen, J2 3 Zhang, B3 Wong, N3 Lo, AWI3 To, KF3 Chan, AWH3 Ng, MHL3 Ho, CYS3 Cheng, SH3 Lai, PBS3 Yu, J3 Ng, HK3 Ling, MT1 Huang, AL2 Cai, XF2 Ko, BCB3 | ||||||
| Issue Date | 2011 | ||||||
| Publisher | American 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?] DOI: http://dx.doi.org/10.1158/0008-5472.CAN-10-4274 | ||||||
| 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. ©2011 AACR. | ||||||
| ISSN | 0008-5472 2011 Impact Factor: 7.856 2011 SCImago Journal Rankings: 1.309 | ||||||
| DOI | http://dx.doi.org/10.1158/0008-5472.CAN-10-4274 | ||||||
| ISI Accession Number ID | WOS:000291637100010
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 | References in Scopus |
| dc.contributor.author | Chen, J | ||||||
|---|---|---|---|---|---|---|---|
| dc.contributor.author | Zhang, B | ||||||
| dc.contributor.author | Wong, N | ||||||
| dc.contributor.author | Lo, AWI | ||||||
| dc.contributor.author | To, KF | ||||||
| dc.contributor.author | Chan, AWH | ||||||
| dc.contributor.author | Ng, MHL | ||||||
| dc.contributor.author | Ho, CYS | ||||||
| dc.contributor.author | Cheng, SH | ||||||
| dc.contributor.author | Lai, PBS | ||||||
| dc.contributor.author | Yu, J | ||||||
| dc.contributor.author | Ng, HK | ||||||
| dc.contributor.author | Ling, MT | ||||||
| dc.contributor.author | Huang, AL | ||||||
| dc.contributor.author | Cai, XF | ||||||
| dc.contributor.author | Ko, BCB | ||||||
| dc.date.accessioned | 2012-06-26T05:58:15Z | ||||||
| dc.date.available | 2012-06-26T05:58:15Z | ||||||
| dc.date.issued | 2011 | ||||||
| dc.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. ©2011 AACR. | ||||||
| dc.description.nature | Link_to_subscribed_fulltext | ||||||
| dc.identifier.citation | Cancer 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.citeulike | 9589274 | ||||||
| dc.identifier.doi | http://dx.doi.org/10.1158/0008-5472.CAN-10-4274 | ||||||
| dc.identifier.epage | 4149 | ||||||
| dc.identifier.isi | WOS:000291637100010
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.issn | 0008-5472 2011 Impact Factor: 7.856 2011 SCImago Journal Rankings: 1.309 | ||||||
| dc.identifier.issue | 12 | ||||||
| dc.identifier.pmid | 21527554 | ||||||
| dc.identifier.scopus | eid_2-s2.0-79958787784 | ||||||
| dc.identifier.spage | 4138 | ||||||
| dc.identifier.uri | http://hdl.handle.net/10722/149765 | ||||||
| dc.identifier.volume | 71 | ||||||
| dc.language | eng | ||||||
| dc.publisher | American Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/ | ||||||
| dc.publisher.place | United States | ||||||
| dc.relation.ispartof | Cancer Research | ||||||
| dc.relation.references | References in Scopus | ||||||
| dc.subject.mesh | Apoptosis | ||||||
| dc.subject.mesh | Carcinoma, Hepatocellular - Genetics - Pathology | ||||||
| dc.subject.mesh | Cell Aging | ||||||
| dc.subject.mesh | Cell Line, Tumor | ||||||
| dc.subject.mesh | Cell Proliferation | ||||||
| dc.subject.mesh | Doxorubicin - Pharmacology | ||||||
| dc.subject.mesh | Gene Expression Regulation, Neoplastic | ||||||
| dc.subject.mesh | Humans | ||||||
| dc.subject.mesh | Immunohistochemistry | ||||||
| dc.subject.mesh | Liver Neoplasms - Genetics - Pathology | ||||||
| dc.subject.mesh | Sirtuin 1 - Analysis - Physiology | ||||||
| dc.subject.mesh | Telomerase - Analysis - Physiology | ||||||
| dc.subject.mesh | Telomere | ||||||
| dc.subject.mesh | Telomere-Binding Proteins - Analysis - Physiology | ||||||
| dc.subject.mesh | Tumor Suppressor Protein P53 - Physiology | ||||||
| dc.subject.mesh | Up-Regulation | ||||||
| dc.title | Sirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth | ||||||
| dc.type | Article |
Author Affiliations
- Institute of Health and Biomedical Innovation
- Chongqing University of Medical Sciences
- Chinese University of Hong Kong