File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Aberrant super-enhancer landscape in human hepatocellular carcinoma

TitleAberrant super-enhancer landscape in human hepatocellular carcinoma
Authors
Issue Date2019
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/
Citation
Hepatology, 2019, v. 69 n. 6, p. 2502-2517 How to Cite?
AbstractHepatocellular carcinoma (HCC) cells exploit an aberrant transcriptional program to sustain their infinite growth and progression. Emerging evidence indicates that the continuous and robust transcription of oncogenes in cancer cells is often driven by super-enhancers (SEs). In this study, we systematically compared the SE landscapes between normal liver and HCC cells and revealed that the cis-acting SE landscape was extensively reprogrammed during liver carcinogenesis. HCC cells acquired SEs at multiple prominent oncogenes to drive their vigorous expression. We identified sphingosine kinase 1 (SPHK1) as an SE-associated oncogene, and we used this gene as an example to illustrate the impact of SEs on the activation of oncogenes in HCC. Concurrently, we also showed that the critical components of the trans-acting SE complex, namely, cyclin-dependent kinase 7 (CDK7), bromodomain-containing protein 4 (BRD4), E1A binding protein P300 (EP300), and mediator complex subunit 1 (MED1), were frequently overexpressed in human HCCs and were associated with the poor prognosis of patients with HCC. Using the CRISPR/Cas9 gene-editing system and specific small-molecule inhibitors, we further demonstrated that HCC cells were highly sensitive to perturbations of the SE complex. The inactivation of CDK7, BRD4, EP300, and MED1 selectively repressed the expression of SE-associated oncogenes in HCC. Finally, we demonstrated that THZ1, which is a small-molecule inhibitor of CDK7, exerted a prominent anticancer effect in both in vitro and in vivo HCC models. Conclusion: The SE landscape and machinery were significantly altered in human HCCs. HCC cells are highly susceptible to perturbations of the SE complex due to the resulting selective suppression of SE-associated oncogenes. Our results suggest that targeting SE complex is a promising therapeutic strategy for HCC treatment. © 2019 by the American Association for the Study of Liver Diseases.
Persistent Identifierhttp://hdl.handle.net/10722/274103
ISSN
2017 Impact Factor: 14.079
2015 SCImago Journal Rankings: 4.752
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorTsang, FH-
dc.contributor.authorLaw, CT-
dc.contributor.authorTang, TCC-
dc.contributor.authorCheng, CL-
dc.contributor.authorChin, DW-
dc.contributor.authorTam, WSV-
dc.contributor.authorWei, L-
dc.contributor.authorWong, CCL-
dc.contributor.authorNg, IOL-
dc.contributor.authorWong, CM-
dc.date.accessioned2019-08-18T14:55:09Z-
dc.date.available2019-08-18T14:55:09Z-
dc.date.issued2019-
dc.identifier.citationHepatology, 2019, v. 69 n. 6, p. 2502-2517-
dc.identifier.issn0270-9139-
dc.identifier.urihttp://hdl.handle.net/10722/274103-
dc.description.abstractHepatocellular carcinoma (HCC) cells exploit an aberrant transcriptional program to sustain their infinite growth and progression. Emerging evidence indicates that the continuous and robust transcription of oncogenes in cancer cells is often driven by super-enhancers (SEs). In this study, we systematically compared the SE landscapes between normal liver and HCC cells and revealed that the cis-acting SE landscape was extensively reprogrammed during liver carcinogenesis. HCC cells acquired SEs at multiple prominent oncogenes to drive their vigorous expression. We identified sphingosine kinase 1 (SPHK1) as an SE-associated oncogene, and we used this gene as an example to illustrate the impact of SEs on the activation of oncogenes in HCC. Concurrently, we also showed that the critical components of the trans-acting SE complex, namely, cyclin-dependent kinase 7 (CDK7), bromodomain-containing protein 4 (BRD4), E1A binding protein P300 (EP300), and mediator complex subunit 1 (MED1), were frequently overexpressed in human HCCs and were associated with the poor prognosis of patients with HCC. Using the CRISPR/Cas9 gene-editing system and specific small-molecule inhibitors, we further demonstrated that HCC cells were highly sensitive to perturbations of the SE complex. The inactivation of CDK7, BRD4, EP300, and MED1 selectively repressed the expression of SE-associated oncogenes in HCC. Finally, we demonstrated that THZ1, which is a small-molecule inhibitor of CDK7, exerted a prominent anticancer effect in both in vitro and in vivo HCC models. Conclusion: The SE landscape and machinery were significantly altered in human HCCs. HCC cells are highly susceptible to perturbations of the SE complex due to the resulting selective suppression of SE-associated oncogenes. Our results suggest that targeting SE complex is a promising therapeutic strategy for HCC treatment. © 2019 by the American Association for the Study of Liver Diseases.-
dc.languageeng-
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/-
dc.relation.ispartofHepatology-
dc.rightsPostprint This is the peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.-
dc.titleAberrant super-enhancer landscape in human hepatocellular carcinoma-
dc.typeArticle-
dc.identifier.emailTsang, FH: fhtsang@HKUCC-COM.hku.hk-
dc.identifier.emailTang, TCC: tcctang@HKUCC-COM.hku.hk-
dc.identifier.emailWei, L: larrywei@HKUCC-COM.hku.hk-
dc.identifier.emailWong, CCL: carmencl@pathology.hku.hk-
dc.identifier.emailNg, IOL: iolng@hku.hk-
dc.identifier.emailWong, CM: jcmwong@hku.hk-
dc.identifier.authorityWong, CCL=rp01602-
dc.identifier.authorityNg, IOL=rp00335-
dc.identifier.authorityWong, CM=rp00231-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/hep.30544-
dc.identifier.pmid30723918-
dc.identifier.scopuseid_2-s2.0-85064575315-
dc.identifier.hkuros301328-
dc.identifier.volume69-
dc.identifier.issue6-
dc.identifier.spage2502-
dc.identifier.epage2517-
dc.identifier.isiWOS:000470926600016-
dc.publisher.placeUnited States-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats