Targeting cis-regulatory elements of FOXO family is a novel therapeutic strategy for induction of leukemia cell differentiation
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Published:2023-09-29
Issue:9
Volume:14
Page:
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ISSN:2041-4889
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Container-title:Cell Death & Disease
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language:en
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Short-container-title:Cell Death Dis
Author:
Kurayoshi KentaORCID, Takase YusukeORCID, Ueno Masaya, Ohta Kumiko, Fuse Kyoko, Ikeda Shuji, Watanabe Takayoshi, Nishida Yuki, Horike Shin-ichi, Hosomichi Kazuyoshi, Ishikawa Yuichi, Tadokoro Yuko, Kobayashi Masahiko, Kasahara Atsuko, Jing Yongwei, Shoulkamy Mahmoud I.ORCID, Meguro-Horike Makiko, Kojima Kensuke, Kiyoi Hitoshi, Sugiyama HiroshiORCID, Nagase Hiroki, Tajima AtsushiORCID, Hirao AtsushiORCID
Abstract
AbstractDifferentiation therapy has been proposed as a promising therapeutic strategy for acute myeloid leukemia (AML); thus, the development of more versatile methodologies that are applicable to a wide range of AML subtypes is desired. Although the FOXOs transcription factor represents a promising drug target for differentiation therapy, the efficacy of FOXO inhibitors is limited in vivo. Here, we show that pharmacological inhibition of a common cis-regulatory element of forkhead box O (FOXO) family members successfully induced cell differentiation in various AML cell lines. Through gene expression profiling and differentiation marker-based CRISPR/Cas9 screening, we identified TRIB1, a complement of the COP1 ubiquitin ligase complex, as a functional FOXO downstream gene maintaining an undifferentiated status. TRIB1 is direct target of FOXO3 and the FOXO-binding cis-regulatory element in the TRIB1 promoter, referred to as the FOXO-responsive element in the TRIB1 promoter (FRE-T), played a critical role in differentiation blockade. Thus, we designed a DNA-binding pharmacological inhibitor of the FOXO-FRE-T interface using pyrrole-imidazole polyamides (PIPs) that specifically bind to FRE-T (FRE-PIPs). The FRE-PIPs conjugated to chlorambucil (FRE-chb) inhibited transcription of TRIB1, causing differentiation in various AML cell lines. FRE-chb suppressed the formation of colonies derived from AML cell lines but not from normal counterparts. Administration of FRE-chb inhibited tumor progression in vivo without remarkable adverse effects. In conclusion, targeting cis-regulatory elements of the FOXO family is a promising therapeutic strategy that induces AML cell differentiation.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology
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