File Download
  Links for fulltext
     (May Require Subscription)
Supplementary

Article: PGC7 promotes tumor oncogenic dedifferentiation through remodeling DNA methylation pattern for key developmental transcription factors

TitlePGC7 promotes tumor oncogenic dedifferentiation through remodeling DNA methylation pattern for key developmental transcription factors
Authors
Issue Date2021
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/cdd
Citation
Cell Death and Differentiation, 2021, v. 28 n. 6, p. 1955-1970 How to Cite?
AbstractPoorly differentiated tumors usually exhibit phenotypes similar to that of their developmental precursor cells. Tumor cells that acquire the lineage progenitor cells feature usually exploit developmental signaling to potentiate cancer progression. However, the underlying molecular events remain elusive. In this study, based on analysis of an in vitro hepatocyte differentiation model, the maternal factor PGC7 (also known as DPPA3, STELLA) was found closely associated with liver development and tumor differentiation in hepatocellular carcinoma (HCC). Expression of PGC7 decreased during hepatocyte maturation and increased progressively from well-differentiated HCCs to poorly differentiated HCCs. Whole-genome methylation sequencing found that PGC7 could induce promoter demethylation of genes related to development. Pathway-based network analysis indicated that downstream targets of PGC7 might form networks associated with developmental transcription factor activation. Overexpression of PGC7 conferred progenitor-like features of HCC cells both in vitro and in vivo. Mechanism studies revealed that PGC7 could impede nuclear translocation of UHRF1, and thus facilitate promoter demethylation of GLI1 and MYCN, both of which are important regulators of HCC self-renewal and differentiation. Depletion or inhibition of GLI1 effectively downregulated MYCN, abolished the effect of PGC7, and sensitized HCC cells to sorafenib treatment. In addition, we found a significant correlation of PGC7 with GLI1/MYCN and lineage differentiation markers in clinical HCC patients. PGC7 expression might drive HCC toward a “dedifferentiated” progenitor lineage through facilitating promoter demethylation of key developmental transcription factors; further inhibition of PGC7/GLI1/MYCN might reverse poorly differentiated HCCs and provide novel therapeutic strategies.
DescriptionHybrid open access
Persistent Identifierhttp://hdl.handle.net/10722/295882
ISSN
2023 Impact Factor: 13.7
2023 SCImago Journal Rankings: 4.102
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYan, Q-
dc.contributor.authorZhang, Y-
dc.contributor.authorFang, X-
dc.contributor.authorLiu, B-
dc.contributor.authorWong, TL-
dc.contributor.authorGong, L-
dc.contributor.authorLiu, S-
dc.contributor.authorYu, D-
dc.contributor.authorLiu, M-
dc.contributor.authorJiang, L-
dc.contributor.authorWang, X-
dc.contributor.authorWei, T-
dc.contributor.authorJia, Y-
dc.contributor.authorLi, L-
dc.contributor.authorSun, L-
dc.contributor.authorTang, Y-
dc.contributor.authorZhou, N-
dc.contributor.authorYuan, YF-
dc.contributor.authorLi, Y-
dc.contributor.authorMa, S-
dc.contributor.authorGuan, XY-
dc.date.accessioned2021-02-08T08:15:22Z-
dc.date.available2021-02-08T08:15:22Z-
dc.date.issued2021-
dc.identifier.citationCell Death and Differentiation, 2021, v. 28 n. 6, p. 1955-1970-
dc.identifier.issn1350-9047-
dc.identifier.urihttp://hdl.handle.net/10722/295882-
dc.descriptionHybrid open access-
dc.description.abstractPoorly differentiated tumors usually exhibit phenotypes similar to that of their developmental precursor cells. Tumor cells that acquire the lineage progenitor cells feature usually exploit developmental signaling to potentiate cancer progression. However, the underlying molecular events remain elusive. In this study, based on analysis of an in vitro hepatocyte differentiation model, the maternal factor PGC7 (also known as DPPA3, STELLA) was found closely associated with liver development and tumor differentiation in hepatocellular carcinoma (HCC). Expression of PGC7 decreased during hepatocyte maturation and increased progressively from well-differentiated HCCs to poorly differentiated HCCs. Whole-genome methylation sequencing found that PGC7 could induce promoter demethylation of genes related to development. Pathway-based network analysis indicated that downstream targets of PGC7 might form networks associated with developmental transcription factor activation. Overexpression of PGC7 conferred progenitor-like features of HCC cells both in vitro and in vivo. Mechanism studies revealed that PGC7 could impede nuclear translocation of UHRF1, and thus facilitate promoter demethylation of GLI1 and MYCN, both of which are important regulators of HCC self-renewal and differentiation. Depletion or inhibition of GLI1 effectively downregulated MYCN, abolished the effect of PGC7, and sensitized HCC cells to sorafenib treatment. In addition, we found a significant correlation of PGC7 with GLI1/MYCN and lineage differentiation markers in clinical HCC patients. PGC7 expression might drive HCC toward a “dedifferentiated” progenitor lineage through facilitating promoter demethylation of key developmental transcription factors; further inhibition of PGC7/GLI1/MYCN might reverse poorly differentiated HCCs and provide novel therapeutic strategies.-
dc.languageeng-
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/cdd-
dc.relation.ispartofCell Death and Differentiation-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titlePGC7 promotes tumor oncogenic dedifferentiation through remodeling DNA methylation pattern for key developmental transcription factors-
dc.typeArticle-
dc.identifier.emailWong, TL: tinlwong@hku.hk-
dc.identifier.emailMa, S: stefma@hku.hk-
dc.identifier.authorityMa, S=rp00506-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/s41418-020-00726-3-
dc.identifier.pmid33500560-
dc.identifier.pmcidPMC8185079-
dc.identifier.scopuseid_2-s2.0-85099765962-
dc.identifier.hkuros321233-
dc.identifier.volume28-
dc.identifier.issue6-
dc.identifier.spage1955-
dc.identifier.epage1970-
dc.identifier.isiWOS:000611917900002-
dc.publisher.placeUnited Kingdom-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats