JQ1, an inhibitor of the epigenetic reader BRD4, suppresses the bidirectional MYC-AP4 axis via multiple mechanisms

Choi,Sung  Kyung; Hong,Seong  Hwi; Kim,Hyuk  Soon; Shin,Chan  Young; Nam,Suk  Woo; Choi,Wahn  Soo; Han,Jeung-Whan; You,Jueng  Soo

doi:10.3892/or.2015.4410

JQ1, an inhibitor of the epigenetic reader BRD4, suppresses the bidirectional MYC-AP4 axis via multiple mechanisms

Authors:
- Sung Kyung Choi
- Seong Hwi Hong
- Hyuk Soon Kim
- Chan Young Shin
- Suk Woo Nam
- Wahn Soo Choi
- Jeung-Whan Han
- Jueng Soo You
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Affiliations: School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea, Functional RNomics Research Center, College of Medicine, Catholic University, Seoul 137-701, Republic of Korea, Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
Published online on: November 11, 2015 https://doi.org/10.3892/or.2015.4410
Pages: 1186-1194

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Abstract

Bromodomain and extra-terminal domain (BET) family proteins are representative epigenetic modulators that read acetylated lysine residues and transfer cellular signals. Recently, the BET protein inhibitor JQ1 was developed and has been extensively studied in many cancer cell types. We demonstrated that JQ1 effectively suppressed the MYC-AP4 axis and induced antitumorigenic effects by targeting a bidirectional positive loop between MYC and AP4 which was first proposed in the present study. MYC and AP4 are the direct targets of BRD4, as demonstrated by chromatin immunoprecipitation (ChIP) assay and BRD4 loss-of-function experiments. Although inhibition of the MYC/MAC dimer suppressed AP4, the efficacy of suppression was not as effective as BRD4 inhibition. Notably, AP4 loss-of-function studies demonstrated that AP4 is a major critical target of JQ1 and that MYC is a novel downstream target of AP4, as demonstrated by AP4 binding to the MYC promoter. Taken together, our results suggest that the epigenetic reader BRD4 is a key mediator of the activated MYC-AP4 axis, which supports the possibility that targeting BET protein is a novel therapeutic strategy for MYC-AP4 axis-activated cancers.

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