Cited by 4Epigenetics and DNA MethylationAcute Myeloid Leukemia ResearchRNA modifications and cancer

A multiomics approach reveals RNA dynamics promote cellular sensitivity to DNA hypomethylation

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Ge, Alex Y., Arab, Abolfazl, Dai, Raymond, Navickas, Albertas, Fish, Lisa, Garcia, Kristle, Asgharian, Hosseinali, Goudreau, Jackson +7 more·2024·Scientific Reports

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Abstract

Epigenetic dysregulation drives many of the hallmarks of cancer by enabling aberrant gene expression programs which underlie cancer cellular plasticity and tumor heterogeneity phenotypes that promote cancer initiation, progression, metastasis and drug resistance 1 . Indeed, one of the key findings of the genomics era in cancer biology has been that most cancer genomes are epigenetically abnormal and mutations in genes that regulate DNA methylation, such as DNMT3A/B , TET1-3 and IDH1/2 , are prevalent 2 , 3 . Together, these observations suggest that epigenetic dysregulation promotes cancer but may also represent a targetable vulnerability. As such, there has been substantial interest in the development of anti-cancer strategies which modulate cancer associated epigenetic programs and dependencies 4 , 5 , 6 . One such promising strategy which has shown success in the context of certain subtypes of acute myeloid leukemia (AML) is to inhibit the activity of key enzymes required for maintenance and regulation of DNA methylation by small molecule drugs, such as decitabine, resulting in global DNA hypomethylation. There is clear evidence of clinical benefit of decitabine treatment for AML patients who have cytogenetic abnormalities associated with unfavorable risk, TP53 mutations or both (defined hereafter as high-risk AML patients) 7 , 8 . Unfortunately, despite this benefit, most AML patients eventually progress following decitabine treatment with a median overall survival of less than 1 year. Problematically, relatively little progress has been made on improving the clinical activity of DNA hypomethylating agents (HMA) such as decitabine in AML or other cancers in part because the molecular determinants of response to HMAs are unclear.

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  • CRISPRi experiments in other cancer cell types (AML, CML, pancreatic cancer and lung cancer cell lines) demonstrated that, unlike PSMA1, PTGES3 is not an essential gene upon knockdown.

    “Furthermore, CRISPRi experiments in other cancer cell types (AML, CML, pancreatic cancer and lung cancer cell lines54–56) demonstrated that, unlike PSMA1, which is a positive control commonly essential gene, PTGES3 is not an essential gene upon knockdown (Extended Data Fig. 10d–g).”

    From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [54]

    The Results section describes CRISPRi screens in AML cell lines, but does not report whether PTGES3 knockdown is nonessential relative to PSMA1. Searches for PTGES3, PSMA1, and the other named cancer cell types found no passage in our copy addressing that comparison. (LLM, conf=0.76)

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Authors
Ge, A. Y., Arab, A., Dai, R., Navickas, A., Fish, L., Garcia, K., Asgharian, H., Goudreau, J., Lee, S., Keenan, K., Pappalardi, M. B., McCabe, M. T., Przybyla, L., Goodarzi, H., & Gilbert, L. A.
Affiliations
  • University of California, San Francisco (US)
  • GlaxoSmithKline (United States) (US)
Corresponding author
  • Goodarzi, Hani
  • Gilbert, Luke A.
Venue
Scientific Reports
Published
2024-10-29
Volume
14
Issue
1
Pages
25940-25940
ISSN
2045-2322 (ISSN-L)
OpenAlex
W4403877082
Cited by
4
References
95
Citations by year
2026: 2 · 2025: 2
FWCI
0.54
Type
journal article
Language
en
Open access
Locations
  • Scientific Reports (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (1s10od028511-01, W81XWH)
  • University of California, San Francisco (1S10OD028511-01)
  • National Cancer Institute (R01CA240984, DP2CA239597, R01CA244634)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
Keywords
DNA hypomethylation, decitabine, acute myeloid leukemia, DNA methylation, RNA dynamics, epigenetic dysregulation, hypomethylating agents, drug response, multi-omics, tumor heterogeneity, TP53 mutation, chromosomal abnormalities

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