title: Histone Acetyltransferase p300/CREB-binding Protein-associated Factor (PCAF) Is Required for All-trans-retinoic Acid-induced Granulocytic Differentiation in Leukemia Cells.
abstract: Differentiation therapy with all-trans-retinoic acid (ATRA) improves the treatment outcome of acute promyelocytic leukemia (APL); however, the molecular mechanism by which ATRA induces granulocytic differentiation remains unclear. We previously reported that the inhibition of the NAD-dependent histone deacetylase (HDAC) SIRT2 induces granulocytic differentiation in leukemia cells, suggesting the involvement of protein acetylation in ATRA-induced leukemia cell differentiation. Herein, we show that p300/CREB-binding protein-associated factor (PCAF), a histone acetyltransferase (HAT), is a prerequisite for ATRA-induced granulocytic differentiation in leukemia cells. We found that PCAF expression was markedly increased in leukemia cell lines (NB4 and HL-60) and primary APL cells during ATRA-induced granulocytic differentiation. Consistent with these results, the expression of PCAF was markedly up-regulated in the bone marrow cells of APL patients who received ATRA-containing chemotherapy. The knockdown of PCAF inhibited ATRA-induced granulocytic differentiation in leukemia cell lines and primary APL cells. Conversely, the overexpression of PCAF induced the expression of the granulocytic differentiation marker CD11b at the mRNA level. Acetylome analysis identified the acetylated proteins after ATRA treatment, and we found that histone H3, a known PCAF acetylation substrate, was preferentially acetylated by the ATRA treatment. Furthermore, we have demonstrated that PCAF is required for the acetylation of histone H3 on the promoter of ATRA target genes, such asCCL2andFGR, and for the expression of these genes in ATRA-treated leukemia cells. These results strongly support our hypothesis that PCAF is induced and activated by ATRA, and the subsequent acetylation of PCAF substrates promotes granulocytic differentiation in leukemia cells. Targeting PCAF and its downstream acetylation targets could serve as a novel therapeutic strategy to overcome all subtypes of AML.
authors.affiliation: From the Department of Hematology.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sunami
authors.affiliation: Department of Transfusion Medicine and Stem Cell Regulation, and.
authors.forename: Marito
authors.initials: M
authors.lastname: Araki
authors.affiliation: From the Department of Hematology.|Leading Center for the Development and Research of Cancer Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan and.
authors.forename: Shin
authors.initials: S
authors.lastname: Kan
authors.affiliation: the Chemical Genetics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ito
authors.affiliation: From the Department of Hematology.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Hironaka
authors.affiliation: Leading Center for the Development and Research of Cancer Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan and.
authors.forename: Misa
authors.initials: M
authors.lastname: Imai
authors.affiliation: Department of Transfusion Medicine and Stem Cell Regulation, and.
authors.forename: Soji
authors.initials: S
authors.lastname: Morishita
authors.affiliation: Department of Transfusion Medicine and Stem Cell Regulation, and.
authors.forename: Akimichi
authors.initials: A
authors.lastname: Ohsaka
authors.affiliation: From the Department of Hematology, komatsun@juntendo.ac.jp.
authors.forename: Norio
authors.initials: N
authors.lastname: Komatsu
mesh_terms: D000107:Acetylation; D039481:CD11b Antigen / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006098:Granulocytes / Q000187:drug effects* / Q000473:pathology; D018922:HL-60 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D014212:Tretinoin / Q000494:pharmacology*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000502:physiology*; D000099224:p300-CBP-Associated Factor
chemical_list: D039481:CD11b Antigen; D006657:Histones; D014212:Tretinoin; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C509295:ITGAM protein, human
keywords: ATRA; PCAF; acute promyelocytic leukemia; differentiation; differentiation therapy; histone acetylase; histone acetylation; leukemia; post-translational modification (PTM)