The WWP1–JARID1B axis sustains acute myeloid leukemia chemoresistance
Abstract
To uncover substrates mediating the oncogenic activity of WWP1 in acute myeloid leukemia (AML), we performed a proteomic analysis that identified the histone demethylase KDM5B /JARID1B as a candidate target. Of note, JARID1B is indispensable for efficient recruitment of several DNA damage repair factors and for damage resolution, thus negatively influencing the sensitivity of cancer cells to chemo- and radiation therapies. Validation of JARID1B as a substrate of WWP1 revealed a positive regulation of JARID1B half-life by WWP1 through the establishment of K63-linked polyubiquitin chains. As a result, downregulation of JARID1B rising from WWP1 inactivation was associated with higher H3K4me3 enrichment at JARID1B target genes in WWP1-depleted relatively to control AML cells. Integration of RNA-seq and H3K4me3 ChIP-seq data uncovered a highly significant overlap between upregulated gene expression and enriched H3K4me3 peaks after shWWP1 inactivation. We confirmed transcriptional activation of JARID1B targets in WWP1-depleted cells, supporting a role for WWP1 in regulating JARID1B activity. Coherently, upon WWP1 inactivation, we observed a defective recruitment of repair proteins after DNA damage, with subsequent reduced DNA damage repair efficiency and enhanced sensitization of AML cells to the cytotoxic activity of chemotherapeutic drugs. All together, these data identify JARID1B as a bona fide target of WWP1 and imply that WWP1-mediated regulation of JARID1B impacts its ability to modify chromatin and to recruit DNA damage repair factors, thus ultimately affecting chemosensitivity of AML cells.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (20)
Claudia Fierro
Department of Experimental Medicine, Tor Vergata Oncoscience Research, University of Rome Tor Vergata
Sara Giovannini
Department of Experimental Medicine, Tor Vergata Oncoscience Research, University of Rome Tor Vergata
Valeria Moriconi
Department of Experimental Medicine, Tor Vergata Oncoscience Research, University of Rome Tor Vergata
Claudia Fiorilli
Department of Experimental Medicine, Tor Vergata Oncoscience Research, University of Rome Tor Vergata
Emanuele Panatta
Department of Experimental Medicine, Tor Vergata Oncoscience Research, University of Rome Tor Vergata
Valentina Frezza
Department of Experimental Medicine, Tor Vergata Oncoscience Research, University of Rome Tor Vergata
Federica Corigliano
Department of Experimental Medicine, Tor Vergata Oncoscience Research, University of Rome Tor Vergata
Rosalba Pecorari
Department of Experimental Medicine, Tor Vergata Oncoscience Research, University of Rome Tor Vergata
Yanan Li
NHC Key Laboratory of Biotechnology for Microbial Drugs
Ji Zhou
Vincenza Simona Delvecchio
Department of Experimental Medicine, Tor Vergata Oncoscience Research, University of Rome Tor Vergata
Artem Smirnov
Department of Experimental Medicine, University of Rome “Tor Vergata”
Jose Manuel Garcia Manteiga
Center for Omics Sciences, Istituti di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute
Andrea Brendolan
Lymphoid stromal cell biology Unit, Division of Experimental Oncology, Istituti di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute
Jinping Zhang
The Centre of Nanoscale Science and Technology and Key Laboratory of Functional Polymer Materials, Institute of Polymer Chemistry, College of Chemistry
Yufang Shi
The Fourth Affiliated Hospital of Soochow University, Institutes for Translational Medicine of Soochow University
Ivano Amelio
Eleonora Candi
Department of Experimental Medicine, University of Rome “Tor Vergata”
Gerry Melino
Department of Experimental Medicine, TOR, University of Rome “Tor Vergata”
Francesca Bernassola
Department of Experimental Medicine, Tor Vergata Oncoscience Research, University of Rome Tor Vergata