Evidence map›Paper›PMID 34897944›Full record

ArticleEMBO reports2022

RASSF1A disrupts the NOTCH signaling axis via SNURF/RNF4-mediated ubiquitination of HES1.

Angelos Papaspyropoulos, Andriani Angelopoulou, Ioanna Mourkioti, Aikaterini Polyzou, Daniela Pankova, Konstantinos Toskas, Simone Lanfredini, Anastasia A Pantazaki, Nefeli Lagopati, Athanassios Kotsinas and 4 more

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

Article in EMBO reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.

0numbers the graph read from it
0cells of the map it votes in
11citing papers in PubMed
1.2field-weighted citation impact, top 21% 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

11 citing papers in PubMed, 16 citations in OpenAlex.

  1. Review
  2. Review
  3. Interrogating the regulatory epigenome of cellular senescence.Cellular and molecular life sciences : CMLS · 2025
    Review
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  5. Review
  6. Article
  7. Article
  8. A GATA2-CDC6 axis modulates androgen receptor blockade-induced senescence in prostate cancer.Journal of experimental & clinical cancer research : CR · 2023
    Article
  9. Review
  10. Article
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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

14 authors at 3 institutions in 2 countries.

Angelos PapaspyropoulosDepartment of Oncology, University of Oxford, Oxford, UK.ORCID 0000-0002-6178-9987
Andriani Angelopoulou *Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens (NKUA), Athens, Greece.
Ioanna Mourkioti *Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens (NKUA), Athens, Greece.
Aikaterini Polyzou *Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens (NKUA), Athens, Greece.
Daniela PankovaDepartment of Oncology, University of Oxford, Oxford, UK.ORCID 0000-0002-3478-8065
Konstantinos ToskasDepartment of Oncology, University of Oxford, Oxford, UK.
Simone LanfrediniDepartment of Oncology, University of Oxford, Oxford, UK.
Anastasia A PantazakiLaboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece.ORCID 0000-0003-3791-6955
Nefeli LagopatiMolecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens (NKUA), Athens, Greece.
Athanassios KotsinasMolecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens (NKUA), Athens, Greece.
Konstantinos EvangelouMolecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens (NKUA), Athens, Greece.
Efstathios ChronopoulosLaboratory for Research of the Musculoskeletal System, KAT General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
Eric O'NeillDepartment of Oncology, University of Oxford, Oxford, UK.ORCID 0000-0002-0060-6278
Vassilis GorgoulisMolecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens (NKUA), Athens, Greece.ORCID 0000-0001-9001-4112
National and Kapodistrian University of Athens · GRUniversity of Oxford · GBAristotle University of Thessaloniki · GR

Funding

Cancer Research UK A19277Medical Research CouncilWellcome Trust
6 · The paper itself

Abstract

RASSF1A promoter methylation has been correlated with tumor dedifferentiation and aggressive oncogenic behavior. Nevertheless, the underlying mechanism of RASSF1A-dependent tumor dedifferentiation remains elusive. Here, we show that RASSF1A directly uncouples the NOTCH-HES1 axis, a key suppressor of differentiation. Interestingly, the crosstalk of RASSF1A with HES1 occurs independently from the signaling route connecting RASSF1A with the Hippo pathway. At the molecular level, we demonstrate that RASSF1A acts as a scaffold essential for the SUMO-targeted E3 ligase SNURF/RNF4 to target HES1 for degradation. The reciprocal relationship between RASSF1A and HES1 is evident across a wide range of human tumors, highlighting the clinical significance of the identified pathway. We show that HES1 upregulation in a RASSF1A-depleted environment renders cells non-responsive to the downstream effects of γ-secretase inhibitors (GSIs) which restrict signaling at the level of the NOTCH receptor. Taken together, we report a mechanism through which RASSF1A exerts autonomous regulation of the critical Notch effector HES1, thus classifying RASSF1A expression as an integral determinant of the clinical effectiveness of Notch inhibitors.

Indexed as

Receptors, NotchSignal TransductionTranscription Factor HES-1Tumor Suppressor ProteinsHumansNuclear ProteinsTranscription FactorsUbiquitinationUbiquitin-Protein LigasesHES1 protein, humanNuclear ProteinsRASSF1 protein, humanReceptors, NotchRNF4 protein, humanSNURF protein, humanTranscription Factor HES-1Transcription FactorsTumor Suppressor ProteinsUbiquitin-Protein Ligasescancer stemnessHippo-Notch signaling crosstalkRASSF1A-HES1-SNURF/RNF4 complexγ-secretase inhibitors (GSIs)

Identifiers

PMID34897944
PMCPMC8811633
OpenAlexW4200535806

What Socratic holds

Textmetadata
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 Socratic graph.