Gadd45a transcriptional induction elicited by the Aurora kinase inhibitor MK-0457 in Bcr-Abl-expressing cells is driven by Oct-1 transcription factor

Manuela Mancini; Elisa Leo; Michela Aluigi; Chiara Marcozzi; Enrica Borsi; Enza Barbieri; Maria Alessandra Santucci

doi:10.1016/j.leukres.2012.03.025

Gadd45a transcriptional induction elicited by the Aurora kinase inhibitor MK-0457 in Bcr-Abl-expressing cells is driven by Oct-1 transcription factor

Leuk Res. 2012 Aug;36(8):1028-34. doi: 10.1016/j.leukres.2012.03.025. Epub 2012 Apr 20.

Authors

Manuela Mancini¹, Elisa Leo, Michela Aluigi, Chiara Marcozzi, Enrica Borsi, Enza Barbieri, Maria Alessandra Santucci

Affiliation

¹ Dipartimento di Ematologia e Scienze Oncologiche Lorenzo e Ariosto Seràgnoli, University of Bologna - Medical School, Bologna, Italy. mancini manu@yahoo.com

PMID: 22521726
DOI: 10.1016/j.leukres.2012.03.025

Abstract

The advantage of Aurora kinase (AK) inhibitors in chronic myeloid leukemia (CML) therapy mostly arises from "off-target" effects on tyrosine kinase (TK) activity of wild type (wt) or mutated Bcr-Abl proteins which drive the disease resistance to imatinib (IM). We proved that the AK inhibitor MK-0457 induces the growth arrest DNA damage-inducible (Gadd) 45a through recruitment of octamer-binding (Oct)-1 transcription factor at a critical promoter region for gene transcription and covalent modifications of histone H3 (lysine 14 acetylation, lysine 9 de-methylation). Such epigenetic chromatin modifications may depict a general mechanism promoting the re-activation of tumor suppressor genes silenced by Bcr-Abl.

Publication types

Evaluation Study
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Aurora Kinases
Cell Cycle Proteins / genetics*
Cell Cycle Proteins / metabolism
Cells, Cultured
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics
Epigenesis, Genetic / drug effects
Fusion Proteins, bcr-abl / genetics
Fusion Proteins, bcr-abl / metabolism
Gene Expression Regulation, Leukemic / drug effects
Histones / metabolism
Humans
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
Mice
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Octamer Transcription Factor-1 / metabolism
Octamer Transcription Factor-1 / physiology*
Piperazines / pharmacology*
Piperazines / therapeutic use
Promoter Regions, Genetic / drug effects
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Protein Serine-Threonine Kinases / antagonists & inhibitors
Transcriptional Activation / drug effects
Up-Regulation / drug effects

Substances

Antineoplastic Agents
Cell Cycle Proteins
GADD45A protein, human
Histones
Nuclear Proteins
Octamer Transcription Factor-1
Piperazines
Protein Kinase Inhibitors
tozasertib
Fusion Proteins, bcr-abl
Aurora Kinases
Protein Serine-Threonine Kinases