Abstract
While all-trans retinoic acid (ATRA) treatment in acute promyelocytic leukemia (APL) has been the paradigm of targeted therapy for oncogenic transcription factors, the underlying mechanisms remain largely unknown, and a significant number of patients still relapse and become ATRA resistant. We identified the histone demethylase PHF8 as a coactivator that is specifically recruited by RARα fusions to activate expression of their downstream targets upon ATRA treatment. Forced expression of PHF8 resensitizes ATRA-resistant APL cells, whereas its downregulation confers resistance. ATRA sensitivity depends on the enzymatic activity and phosphorylation status of PHF8, which can be pharmacologically manipulated to resurrect ATRA sensitivity to resistant cells. These findings provide important molecular insights into ATRA response and a promising avenue for overcoming ATRA resistance.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Drug Resistance, Neoplasm
-
Histone Demethylases / genetics
-
Histone Demethylases / metabolism*
-
Histones
-
Humans
-
Leukemia, Promyelocytic, Acute / drug therapy*
-
Leukemia, Promyelocytic, Acute / metabolism*
-
Mice
-
Mice, Inbred NOD
-
Mice, SCID
-
Neoplasm Proteins / metabolism
-
Okadaic Acid / pharmacology
-
Oncogene Proteins, Fusion / metabolism
-
Phosphorylation
-
RNA Interference
-
RNA, Small Interfering
-
Receptors, Retinoic Acid / genetics
-
Receptors, Retinoic Acid / metabolism*
-
Retinoic Acid Receptor alpha
-
Signal Transduction
-
Transcription Factors / genetics
-
Transcription Factors / metabolism*
-
Transcription, Genetic
-
Tretinoin / pharmacology*
-
Tumor Cells, Cultured
Substances
-
Histones
-
Neoplasm Proteins
-
Oncogene Proteins, Fusion
-
RARA protein, human
-
RNA, Small Interfering
-
Rara protein, mouse
-
Receptors, Retinoic Acid
-
Retinoic Acid Receptor alpha
-
Transcription Factors
-
Okadaic Acid
-
Tretinoin
-
Histone Demethylases
-
PHF8 protein, mouse