Evidence map›Paper›PMID 29858058›Full record

ArticleMolecular therapy. Nucleic acids2018

Epigenetic Targeting of Granulin in Hepatoma Cells by Synthetic CRISPR dCas9 Epi-suppressors.

Hong Wang, Rui Guo, Zhonghua Du, Ling Bai, Lingyu Li, Jiuwei Cui, Wei Li, Andrew R Hoffman, Ji-Fan Hu

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular therapy. Nucleic acids, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.

0numbers the graph read from it
0cells of the map it votes in
42citing papers in PubMed
3.2field-weighted citation impact, top 7% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

42 citing papers in PubMed, 75 citations in OpenAlex.

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  19. Advances in CRISPR therapeutics.Nature reviews. Nephrology · 2023
    Review
  20. CRISPR-Based Tools for Fighting Rare Diseases.Life (Basel, Switzerland) · 2022
    Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 2 institutions in 2 countries.

Hong WangStem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, China; VA Palo Alto Health Care System and Stanford University Medical School, Palo Alto, CA 94304, USA.
Rui GuoClinical Laboratory, First Affiliated Hospital, Jilin University, Changchun, China; VA Palo Alto Health Care System and Stanford University Medical School, Palo Alto, CA 94304, USA.
Zhonghua DuStem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, China.
Ling BaiStem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, China.
Lingyu LiStem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, China.
Jiuwei CuiStem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, China. Electronic address: cuijiuwei@jlu.edu.cn.
Wei LiStem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, China. Electronic address: drweili@yahoo.com.
Andrew R HoffmanVA Palo Alto Health Care System and Stanford University Medical School, Palo Alto, CA 94304, USA. Electronic address: arhoffman@stanford.edu.
Ji-Fan HuStem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, China; VA Palo Alto Health Care System and Stanford University Medical School, Palo Alto, CA 94304, USA. Electronic address: jifan@stanford.edu.
Jilin University · CNVA Palo Alto Health Care System · US

Funding

The Role of Long Noncoding RNAs in CancerI01BX002905 · VA · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · PI HOFFMAN, ANDREW R · 2016 to 2023
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BLRD VA I01 BX002905
6 · The paper itself

Abstract

The CRISPR-associated Cas9 system can modulate disease-causing alleles both in vivo and ex vivo, raising the possibility of therapeutic genome editing. In addition to gene targeting, epigenetic modulation by the catalytically inactive dCas9 may also be a potential form of cancer therapy. Granulin (GRN), a potent pluripotent mitogen and growth factor that promotes cancer progression by maintaining self-renewal of hepatic stem cancer cells, is upregulated in hepatoma tissues and is associated with decreased tumor survival in patients with hepatoma. We synthesized a group of dCas9 epi-suppressors to target GRN by tethering the C terminus of dCas9 with three epigenetic suppressor genes: DNMT3a (DNA methyltransferase), EZH2 (histone 3 lysine 27 methyltransferase), and KRAB (the Krüppel-associated box transcriptional repression domain). In conjunction with guide RNAs (gRNAs), the dCas9 epi-suppressors caused significant decreases in GRN mRNA abundance in Hep3B hepatoma cells. These dCas9 epi-suppressors initiated de novo CpG DNA methylation in the GRN promoter, and they produced histone codes that favor gene suppression, including decreased H3K4 methylation, increased H3K9 methylation, and enhanced HP1a binding. Epigenetic knockdown of GRN led to the inhibition of cell proliferation, decreased tumor sphere formation, and reduced cell invasion. These changes were achieved at least partially through the MMP/TIMP pathway. This study thus demonstrates the potential utility of using dCas9 epi-suppressors in the development of epigenetic targeting against tumors.

Indexed as

cancerCRISPR dCas9DNA methylationDNMT3aepigenetic targetingEZH2hepatomahistone methylationKRAB

Identifiers

PMID29858058
PMCPMC5849805
OpenAlexW2782850890

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.