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Class I histone deacetylase inhibition is synthetic lethal with BRCA1 deficiency in breast cancer cells
Zhang,Baoyuan1; Lyu,Junfang1; Yang,Eun Ju1; Liu,Yifan1; Wu,Changjie1; Pardeshi,Lakhansing2; Tan,Kaeling2; Chen,Qiang1,2; Xu,Xiaoling1,2; Deng,Chu Xia1,2; Shim,Joong Sup1,2
2020-04-01
Source PublicationActa Pharmaceutica Sinica B
ISSN2211-3835
Volume10Issue:4Pages:615-627
Abstract

Breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene, which is frequently mutated in breast and ovarian cancers. BRCA1 plays a key role in the homologous recombination directed DNA repair, allowing its deficiency to act as a therapeutic target of DNA damaging agents. In this study, we found that inhibition of the class I histone deacetylases (HDAC) exhibited synthetic lethality with BRCA1 deficiency in breast cancer cells. Transcriptome profiling and validation study showed that HDAC inhibition enhanced the expression of thioredoxin interaction protein (TXNIP), causing reactive oxygen species (ROS)-mediated DNA damage. This effect induced preferential apoptosis in BRCA1 breast cancer cells where DNA repair system is compromised. Two animal experiments and gene expression-associated patients’ survival analysis further confirmed in vivo synthetic lethality between BRCA1 and HDAC. Finally, the combination of inhibitors of HDAC and bromodomain and extra-terminal motif (BET), another BRCA1 synthetic lethality target that also works through oxidative stress-mediated DNA damage, showed a strong anticancer effect in BRCA1 breast cancer cells. Together, this study provides a new therapeutic strategy for BRCA1-deficient breast cancer by targeting two epigenetic machineries, HDAC and BET.

KeywordBrca1 Breast Cancer Dna Damage Hdac Histone Deacetylase Reactive Oxygen Species Synthetic Lethality
DOI10.1016/j.apsb.2019.08.008
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000526087100004
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Cited Times [WOS]:5   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorShim,Joong Sup
Affiliation1.Cancer Centre,Faculty of Health Sciences,University of Macau,China
2.Institute of Translational Medicine,Faculty of Health Sciences,University of Macau,China
First Author AffilicationCancer Centre
Corresponding Author AffilicationCancer Centre;  Faculty of Health Sciences
Recommended Citation
GB/T 7714
Zhang,Baoyuan,Lyu,Junfang,Yang,Eun Ju,et al. Class I histone deacetylase inhibition is synthetic lethal with BRCA1 deficiency in breast cancer cells[J]. Acta Pharmaceutica Sinica B,2020,10(4):615-627.
APA Zhang,Baoyuan,Lyu,Junfang,Yang,Eun Ju,Liu,Yifan,Wu,Changjie,Pardeshi,Lakhansing,Tan,Kaeling,Chen,Qiang,Xu,Xiaoling,Deng,Chu Xia,&Shim,Joong Sup.(2020).Class I histone deacetylase inhibition is synthetic lethal with BRCA1 deficiency in breast cancer cells.Acta Pharmaceutica Sinica B,10(4),615-627.
MLA Zhang,Baoyuan,et al."Class I histone deacetylase inhibition is synthetic lethal with BRCA1 deficiency in breast cancer cells".Acta Pharmaceutica Sinica B 10.4(2020):615-627.
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