ArticleOncotarget2016
A novel PAD4/SOX4/PU.1 signaling pathway is involved in the committed differentiation of acute promyelocytic leukemia cells into granulocytic cells.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 32 citations in OpenAlex.
- Beyond the Human Body: Models for Studying Neutrophil Biology.Immunology and cell biology · 2026Review
- The role of epigenetic regulation in cuproptosis, ferroptosis and NETosis in the pathogenesis of autoimmune diseases.Apoptosis : an international journal on programmed cell death · 2025Review
- How histone modifications influence cellular radiosensitivity: Pharmaceutically targeting epigenetic regulators as a promising avenue to overcome radioresistance.Acta pharmaceutica Sinica. B · 2025Review
- Reversing the Warburg Effect: YW3-56 Induces Leukemia Differentiation via AKT-Mediated Glucose Metabolic Reprogramming.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Roles of PADI4 in the expression of cytokines involved in inflammation and adhesion in differentiated NB4 cells treated with ATRA.Experimental and therapeutic medicine · 2023Article
- Article
- PAD4 and Its Inhibitors in Cancer Progression and Prognosis.Pharmaceutics · 2022Review
- miR-let-7c-3p targeting on Egr-1 contributes to the committed differentiation of leukemia cells into monocyte/macrophages.Oncology letters · 2022Article
- Dexamethasone, but Not Vitamin D or A, Dampens the Inflammatory Neutrophil Response to Protect At-risk COVID-19 Patients.Immune network · 2022Article
- Histone citrullination: a new target for tumors.Molecular cancer · 2021Review
- Differentiation of HL-60 cells in serum-free hematopoietic cell media enhances the production of neutrophil extracellular traps.Experimental and therapeutic medicine · 2021Article
- Effects of an Environmentally Relevant Mixture of Organophosphate Esters Derived From House Dust on Endochondral Ossification in Murine Limb Bud Cultures.Toxicological sciences : an official journal of the Society of Toxicology · 2021Article
- Studying Neutrophil Function in vitro: Cell Models and Environmental Factors.Journal of inflammation research · 2021Review
- Peptidylarginine Deiminase IV Regulates Breast Cancer Stem Cells via a Novel Tumor Cell-Autonomous Suppressor Role.Cancer research · 2020Article
- Mathematical models of amino acid panel for assisting diagnosis of children acute leukemia.Journal of translational medicine · 2019Article
- Overexpression of SOX4 correlates with poor prognosis of acute myeloid leukemia and is leukemogenic in zebrafish.Blood cancer journal · 2017Article
- RARα2 and PML-RAR similarities in the control of basal and retinoic acid induced myeloid maturation of acute myeloid leukemia cells.Oncotarget · 2017Article
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
All-trans retinoic acid (ATRA) treatment yields cure rates > 80% through proteasomal degradation of the PML-RARα fusion protein that typically promotes acute promyelocytic leukemia (APL). However, recent evidence indicates that ATRA can also promote differentiation of leukemia cells that are PML-RARα negative, such as HL-60 cells. Here, gene expression profiling of HL-60 cells was used to investigate the alternative mechanism of impaired differentiation in APL. The expression of peptidylarginine deiminase 4 (PADI4), encoding PAD4, a protein that post-translationally converts arginine into citrulline, was restored during ATRA-induced differentiation. We further identified that hypermethylation in the PADI4 promoter was associated with its transcriptional repression in HL-60 and NB4 (PML-RARα positive) cells. Functionally, PAD4 translocated into the nucleus upon ATRA exposure and promoted ATRA-mediated differentiation. Mechanistic studies using RNAi knockdown or electroporation-mediated delivery of PADI4, along with chromatin immunoprecipitation, helped identify PU.1 as an indirect target and SOX4 as a direct target of PAD4 regulation. Indeed, PAD4 regulates SOX4-mediated PU.1 expression, and thereby the differentiation process, in a SOX4-dependent manner. Taken together, our results highlight an association between PAD4 and DNA hypermethylation in APL and demonstrate that targeting PAD4 or regulating its downstream effectors may be a promising strategy to control differentiation in the clinic.
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Registered trials
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.