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

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

doi:10.1016/j.apsb.2019.08.008

Cited by 25 publications

(22 citation statements)

References 55 publications

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“…As such, curcumin has been proposed as a component of combinatorial therapies for multidrug-resistant MM [ 77 ]. In the case of DHC, its synthetic lethality toward BRCA1-deficient breast cancer lines [ 78 ] also indicates its potential in combinatorial cancer therapy. Therefore, our RAD52 -overexpressing proteasome mutants may serve as models for research into HDR inhibitors that reverse the multidrug-resistant phenotypes of hard-to-treat malignancies.…”

Section: Discussionmentioning

confidence: 99%

Yeast Rpn4 Links the Proteasome and DNA Repair via RAD52 Regulation

Spasskaya

Nadolinskaia

Tutyaeva

et al. 2020

IJMS

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Environmental and intracellular factors often damage DNA, but multiple DNA repair pathways maintain genome integrity. In yeast, the 26S proteasome and its transcriptional regulator and substrate Rpn4 are involved in DNA damage resistance. Paradoxically, while proteasome dysfunction may induce hyper-resistance to DNA-damaging agents, Rpn4 malfunction sensitizes yeasts to these agents. Previously, we proposed that proteasome inhibition causes Rpn4 stabilization followed by the upregulation of Rpn4-dependent DNA repair genes and pathways. Here, we aimed to elucidate the key Rpn4 targets responsible for DNA damage hyper-resistance in proteasome mutants. We impaired the Rpn4-mediated regulation of candidate genes using the CRISPR/Cas9 system and tested the sensitivity of mutant strains to 4-NQO, MMS and zeocin. We found that the separate or simultaneous deregulation of 19S or 20S proteasome subcomplexes induced MAG1, DDI1, RAD23 and RAD52 in an Rpn4-dependent manner. Deregulation of RAD23, DDI1 and RAD52 sensitized yeast to DNA damage. Genetic, epigenetic or dihydrocoumarin-mediated RAD52 repression restored the sensitivity of the proteasome mutants to DNA damage. Our results suggest that the Rpn4-mediated overexpression of DNA repair genes, especially RAD52, defines the DNA damage hyper-resistant phenotype of proteasome mutants. The developed yeast model is useful for characterizing drugs that reverse the DNA damage hyper-resistance phenotypes of cancers.

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Section: Discussionmentioning

confidence: 99%

Yeast Rpn4 Links the Proteasome and DNA Repair via RAD52 Regulation

Spasskaya

Nadolinskaia

Tutyaeva

et al. 2020

IJMS

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“…The inhibition of TXNIP promotes tumor cell proliferation, EMT, and metastasis [ 204 , 205 , 206 ]. However, TXNIP can be upregulated by inhibiting histone deacetylases [ 207 , 208 ], bromodomain and extra-terminal domain [ 209 ], phosphatidylinositol-3-kinase (PI3K)/AKT pathway [ 210 ], the downregulation of HER1/2 [ 163 ], or focal adhesion kinase [ 211 ]. The poor survival of triple-negative breast cancer patients correlates with elevated c-MYC and decreased expression of TXNIP, which is probably due to c-MYC binding to the TXNIP promoter [ 177 ].…”

Section: Redox Homeostasismentioning

confidence: 99%

The NRF2, Thioredoxin, and Glutathione System in Tumorigenesis and Anticancer Therapies

et al. 2020

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Cancer remains an elusive, highly complex disease and a global burden. Constant change by acquired mutations and metabolic reprogramming contribute to the high inter- and intratumor heterogeneity of malignant cells, their selective growth advantage, and their resistance to anticancer therapies. In the modern era of integrative biomedicine, realizing that a personalized approach could benefit therapy treatments and patients’ prognosis, we should focus on cancer-driving advantageous modifications. Namely, reactive oxygen species (ROS), known to act as regulators of cellular metabolism and growth, exhibit both negative and positive activities, as do antioxidants with potential anticancer effects. Such complexity of oxidative homeostasis is sometimes overseen in the case of studies evaluating the effects of potential anticancer antioxidants. While cancer cells often produce more ROS due to their increased growth-favoring demands, numerous conventional anticancer therapies exploit this feature to ensure selective cancer cell death triggered by excessive ROS levels, also causing serious side effects. The activation of the cellular NRF2 (nuclear factor erythroid 2 like 2) pathway and induction of cytoprotective genes accompanies an increase in ROS levels. A plethora of specific targets, including those involved in thioredoxin (TRX) and glutathione (GSH) systems, are activated by NRF2. In this paper, we briefly review preclinical research findings on the interrelated roles of the NRF2 pathway and TRX and GSH systems, with focus given to clinical findings and their relevance in carcinogenesis and anticancer treatments.

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“…For some tumor cells, BRCA1 and BRCA2 gene mutation, resulting in the cells can not complete DNA repair well. At this time, if a DNA repair inhibitor is applied to tumor cells, it will produce a synthetic lethal effect to kill tumor cells 27 , 28 , 29 . Although this strategy is very effective, BRCA1/2 mutations account for only 2%–3% of all breast cancers 30 .…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy

Chang

Sun

Shi

et al. 2021

Acta Pharmaceutica Sinica B

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This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragment-based combinatorial screening and activity assays that together led to the chemical optimization. Among these compounds, 19d was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1, respectively. Compound 19d was further shown to efficiently modulate the expression of BRD4 and PARP1. Subsequently, compound 19d was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase. Following pharmacokinetic studies, compound 19d showed its antitumor activity in breast cancer susceptibility gene 1/2 ( BRCA1/2 ) wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight. These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer.

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

Cited by 25 publications

References 55 publications

Yeast Rpn4 Links the Proteasome and DNA Repair via RAD52 Regulation

Yeast Rpn4 Links the Proteasome and DNA Repair via RAD52 Regulation

The NRF2, Thioredoxin, and Glutathione System in Tumorigenesis and Anticancer Therapies

Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy

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