CRTC1 transcriptional coactivator is required for hepatitis B virus gene expression and replication
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POSTER PRESENTATION Open Access CRTC1 transcriptional coactivator is required for hepatitis B virus gene expression and replication Hei-Man Vincent Tang, Wei-Wei Gao, Chi-Ping Chan, Kin-Hang Kok, Dong-Yan Jin * From Metabolism, Diet and Disease 2014: Cancer and metabolism Washington DC, USA. 28-30 May 2014 Background Chronic hepatitis B virus (HBV) infection occurs in over 400 million people worldwide, 15-40% of whom will term- inally develop severe liver diseases including hepatocellular carcinoma. Although development of HCC is a multi-step process, high HBV DNA level is a major risk factor for disease progression. Transcription of HBV from the cccDNA template is essential for its replication and requires CREB transcription factor, a master regulator of cell metabolism. However, transcriptional coactivators that facilitate CREB-dependent activation of HBV transcription remain to be identified and characterized. Results In this study we demonstrate that cellular CRTC tran- scriptional coactivators, which also play important roles in liver metabolism, are required for HBV transcription and replication. CRTC1 expression was elevated in HBV-positive hepatoma cells and liver tissues. Ectopic expression of CRTC1 in HepG2 hepatoma cells stimu- lated preS2/S promoter activity of HBV, whereas overex- pression of a dominant inactive form of CRTC1 resulted in suppression of activity. CRTC1 interacts with CREB and they are mutually required for the recruitment to preS2/S promoter and the activation of HBV transcrip- tion. The expression of pregenomic RNA (pgRNA) and the level of cccDNA were upregulated when CRTC1 was overexpressed, whereas the levels of pgRNA, cccDNA and HBsAg were diminished when CRTC1 was compromised. In addition, HBV transactivator protein HBx stabilized CRTC1 and promoted its activity on HBV transcription. Conclusion Our work reveals an essential role of CRTC1 in HBV transcription and an unrecognized link between liver metabolism and HBV oncogenesis mediated through a shared transcriptional coactivator. Acknowledgements The work was supported by Hong Kong HMRF (12111052 and 13121052) and SK YEE Medical Fund (2011). Published: 28 May 2014 References 1. Siu YT, Chin KT, Siu KL, Choy EYW, Jeang KT, Jin DY: TORC1 and TORC2 coactivators are required for Tax activation of the human T-cell leukemia virus type 1 long terminal repeats. J Virol 2006, 80:7052-7059. 2. Siu YT, Jin DY: CREB - a real culprit in oncogenesis. FEBS J 2007, 274:3224-3232. 3. Tang HMV, Gao WW, Chan CP, Siu YT, Wong CM, Kok KH, Ching YP, Takemori H, Jin DY: LKB1 tumor suppressor and salt-inducible kinases negatively regulate human T-cell leukemia virus type 1 transcription. Retrovirology 2013, 10:40. doi:10.1186/2049-3002-2-S1-P31 Cite this article as: Tang et al.: CRTC1 transcriptional coactivator is required for hepatitis B virus gene expression and replication. Cancer & Metabolism 2014 2(Suppl 1):P31. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit Department of Biochemistry and State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong Tang et al. Cancer & Metabolism 2014, 2(Suppl 1):P31 http://www.cancerandmetabolism.com/content/2/S1/P31 Cancer & Metabolism © 2014 Tang et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Transcript of CRTC1 transcriptional coactivator is required for hepatitis B virus gene expression and replication
POSTER PRESENTATION Open Access
CRTC1 transcriptional coactivator is required forhepatitis B virus gene expression and replicationHei-Man Vincent Tang, Wei-Wei Gao, Chi-Ping Chan, Kin-Hang Kok, Dong-Yan Jin*
From Metabolism, Diet and Disease 2014: Cancer and metabolismWashington DC, USA. 28-30 May 2014
BackgroundChronic hepatitis B virus (HBV) infection occurs in over400 million people worldwide, 15-40% of whom will term-inally develop severe liver diseases including hepatocellularcarcinoma. Although development of HCC is a multi-stepprocess, high HBV DNA level is a major risk factor fordisease progression. Transcription of HBV from thecccDNA template is essential for its replication andrequires CREB transcription factor, a master regulator ofcell metabolism. However, transcriptional coactivators thatfacilitate CREB-dependent activation of HBV transcriptionremain to be identified and characterized.
ResultsIn this study we demonstrate that cellular CRTC tran-scriptional coactivators, which also play important rolesin liver metabolism, are required for HBV transcriptionand replication. CRTC1 expression was elevated inHBV-positive hepatoma cells and liver tissues. Ectopicexpression of CRTC1 in HepG2 hepatoma cells stimu-lated preS2/S promoter activity of HBV, whereas overex-pression of a dominant inactive form of CRTC1 resultedin suppression of activity. CRTC1 interacts with CREBand they are mutually required for the recruitment topreS2/S promoter and the activation of HBV transcrip-tion. The expression of pregenomic RNA (pgRNA) andthe level of cccDNA were upregulated when CRTC1was overexpressed, whereas the levels of pgRNA,cccDNA and HBsAg were diminished when CRTC1 wascompromised. In addition, HBV transactivator proteinHBx stabilized CRTC1 and promoted its activity onHBV transcription.
ConclusionOur work reveals an essential role of CRTC1 in HBVtranscription and an unrecognized link between livermetabolism and HBV oncogenesis mediated through ashared transcriptional coactivator.
AcknowledgementsThe work was supported by Hong Kong HMRF (12111052 and 13121052)and SK YEE Medical Fund (2011).
Published: 28 May 2014
References1. Siu YT, Chin KT, Siu KL, Choy EYW, Jeang KT, Jin DY: TORC1 and TORC2
coactivators are required for Tax activation of the human T-cellleukemia virus type 1 long terminal repeats. J Virol 2006, 80:7052-7059.
2. Siu YT, Jin DY: CREB - a real culprit in oncogenesis. FEBS J 2007,274:3224-3232.
3. Tang HMV, Gao WW, Chan CP, Siu YT, Wong CM, Kok KH, Ching YP,Takemori H, Jin DY: LKB1 tumor suppressor and salt-inducible kinasesnegatively regulate human T-cell leukemia virus type 1 transcription.Retrovirology 2013, 10:40.
doi:10.1186/2049-3002-2-S1-P31Cite this article as: Tang et al.: CRTC1 transcriptional coactivator isrequired for hepatitis B virus gene expression and replication. Cancer &Metabolism 2014 2(Suppl 1):P31.
Submit your next manuscript to BioMed Centraland take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at www.biomedcentral.com/submitDepartment of Biochemistry and State Key Laboratory for Liver Research,
The University of Hong Kong, Pokfulam, Hong Kong
Tang et al. Cancer & Metabolism 2014, 2(Suppl 1):P31http://www.cancerandmetabolism.com/content/2/S1/P31 Cancer &
Metabolism
© 2014 Tang et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproductionin any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
