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Class I histone deacetylase inhibition is synthetic lethal with BRCA1 deficiency in breast cancer cells.

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.

SUBMITTER: Zhang B

PROVIDER: S-EPMC7161709 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Class I histone deacetylase inhibition is synthetic lethal with BRCA1 deficiency in breast cancer cells.

Zhang Baoyuan B Lyu Junfang J Yang Eun Ju EJ Liu Yifan Y Wu Changjie C Pardeshi Lakhansing L Tan Kaeling K Chen Qiang Q Xu Xiaoling X Deng Chu-Xia CX Shim Joong Sup JS

Acta pharmaceutica Sinica. B 20190905 4

Breast cancer susceptibility gene 1 (<i>BRCA1</i>) 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 sho ...[more]

PMID: 32322466

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Project description:BACKGROUND:Hemorrhagic shock (HS) followed by a subsequent insult ("second hit") often initiates an exaggerated systemic inflammatory response and multiple organ failure. We have previously demonstrated that valproic acid, a pan histone deacetylase inhibitor, could improve survival in a rodent "two-hit" model. In the present study, our goal was to determine whether selective inhibition of histone deacetylase 6 with Tubastatin A (Tub-A) could prolong survival in a two-hit model where HS was followed by sepsis from cecal ligation and puncture (CLP). METHODS:C57Bl/6J mice were subjected to sublethal HS (30% blood loss) and then randomly divided into two groups (n = 13 per group) such as Tub-A group (treatment) and vehicle (VEH) group (control). The Tub-A group was given an intraperitoneal injection of Tub-A (70 mg/kg) dissolved in dimethyl sulfoxide (DMSO). The VEH group was injected with DMSO (1 ?l/g body weight). After 24 h, all mice were subjected CLP followed immediately by another dose of Tub-A or DMSO. Survival was monitored for 10 d. In a parallel study, peritoneal irrigation fluid and liver tissue from Tub-A- or DMSO-treated mice were collected 3 h after CLP. Enzyme-linked immunosorbent assay was performed to quantify activity of the myeloperoxidase and concentrations of tumor necrosis factor-alpha (TNF-?) and interleukin 6 (IL-6) in the peritoneal irrigation fluid. RNA was isolated from the liver tissue, and real-time polymerase chain reaction was performed to measure relative messenger RNA levels of TNF-? and IL-6. RESULTS:Treatment with Tub-A significantly improved survival compared with that of the control (69.2% versus 15.4%). In addition, Tub-A significantly suppressed myeloperoxidase activity (169.9 ± 8.4 ng/mL versus 70.4 ± 17.4 ng/mL; P < 0.01) and reduced levels of cytokines TNF-? and IL-6 in the peritoneal fluid (TNF-?: 105.7 ± 4.7 versus 7.4 ± 2.4 pg/mL; IL-6: 907.4 ± 2.3 versus 483.6 ± 1.6 pg/mL; P < 0.01) compared with those in the VEH control. Gene expression measured by real-time polymerase chain reaction confirmed that Tub-A inhibits transcription of TNF-? and IL-6. CONCLUSIONS:Tub-A treatment significantly improves survival, attenuates inflammation, and downregulates TNF-? and IL-6 gene expression in a rodent two-hit model.

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Class I histone deacetylase inhibition is synthetic lethal with BRCA1 deficiency in breast cancer cells.

Publications

Class I histone deacetylase inhibition is synthetic lethal with BRCA1 deficiency in breast cancer cells.

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