The DNA Endonuclease Mus81 Regulates ZEB1 Expression and Serves as a Target of BET4 Inhibitors in Gastric Cancer

Yin, Yuping; Liu, Weizhen; Shen, Qian; Zhang, Peng; Wang, Lulu; Tao, Ruikang; Li, Hang; Ma, Xianxiong; Zeng, Xiangyu; Cheong, Jae Ho; Song, Shumei; Ajani, Jaffer A.; Mills, Gordon B.; Tao, Kaixiong; Peng, Guang

doi:10.1158/1535-7163.mct-18-0833

Cited by 15 publications

(19 citation statements)

References 45 publications

(42 reference statements)

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“…Multiple studies have also focused on BET inhibitors in cancer. In this context, it was observed that the DNA endonuclease Mus81, which regulates ZEB1, may be targeted by BET4 inhibitors (Yin et al, 2019). In general, miRNA-based therapeutic options targeting ZEB1 might represent promising tools for targeting ZEB1 but need to be further developed, and delivery methods and therapeutic agent stability should also be investigated with priority.…”

Section: Discussionmentioning

confidence: 99%

ZEB1: A Critical Regulator of Cell Plasticity, DNA Damage Response, and Therapy Resistance

Drápela

Bouchal

Jolly

et al. 2020

Front. Mol. Biosci.

120

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The predominant way in which conventional chemotherapy kills rapidly proliferating cancer cells is the induction of DNA damage. However, chemoresistance remains the main obstacle to therapy effectivity. An increasing number of studies suggest that epithelial-to-mesenchymal transition (EMT) represents a critical process affecting the sensitivity of cancer cells to chemotherapy. Zinc finger E-box binding homeobox 1 (ZEB1) is a prime element of a network of transcription factors controlling EMT and has been identified as an important molecule in the regulation of DNA damage, cancer cell differentiation, and metastasis. Recent studies have considered upregulation of ZEB1 as a potential modulator of chemoresistance. It has been hypothesized that cancer cells undergoing EMT acquire unique properties that resemble those of cancer stem cells (CSCs). These stem-like cells manifest enhanced DNA damage response (DDR) and DNA repair capacity, self-renewal, or chemoresistance. In contrast, functional experiments have shown that ZEB1 induces chemoresistance regardless of whether other EMT-related changes occur. ZEB1 has also been identified as an important regulator of DDR by the formation of a ZEB1/p300/PCAF complex and direct interaction with ATM kinase, which has been linked to radioresistance. Moreover, ATM can directly phosphorylate ZEB1 and enhance its stability. Downregulation of ZEB1 has also been shown to reduce the abundance of CHK1, an effector kinase of DDR activated by ATR, and to induce its ubiquitin-dependent degradation. In this perspective, we focus on the role of ZEB1 in the regulation of DDR and describe the mechanisms of ZEB1-dependent chemoresistance.

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Section: Discussionmentioning

confidence: 99%

ZEB1: A Critical Regulator of Cell Plasticity, DNA Damage Response, and Therapy Resistance

Drápela

Bouchal

Jolly

et al. 2020

Front. Mol. Biosci.

120

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“…Genetic polymorphisms in MLH1 have also been associated with male infertility [178]. In addition, some of these DNA-remodeling enzymes, such as for example MUS81, are also emerging as potential targets in chemotherapeutic intervention [179][180][181][182]. Thus, advances in yeast studies have important implications in understanding the basis of human disorders linked to genome instability.…”

Section: Discussionmentioning

confidence: 99%

Resolvases, Dissolvases, and Helicases in Homologous Recombination: Clearing the Road for Chromosome Segregation

San-Segundo

Clemente‐Blanco

2020

Genes

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The execution of recombinational pathways during the repair of certain DNA lesions or in the meiotic program is associated to the formation of joint molecules that physically hold chromosomes together. These structures must be disengaged prior to the onset of chromosome segregation. Failure in the resolution of these linkages can lead to chromosome breakage and nondisjunction events that can alter the normal distribution of the genomic material to the progeny. To avoid this situation, cells have developed an arsenal of molecular complexes involving helicases, resolvases, and dissolvases that recognize and eliminate chromosome links. The correct orchestration of these enzymes promotes the timely removal of chromosomal connections ensuring the efficient segregation of the genome during cell division. In this review, we focus on the role of different DNA processing enzymes that collaborate in removing the linkages generated during the activation of the homologous recombination machinery as a consequence of the appearance of DNA breaks during the mitotic and meiotic programs. We will also discuss about the temporal regulation of these factors along the cell cycle, the consequences of their loss of function, and their specific role in the removal of chromosomal links to ensure the accurate segregation of the genomic material during cell division.

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“…The IHC scores were calculated as described previously [26]. The staining intensity scores were as follows: 0 (negative), 1 (weak), 2 (medium), and 3 (strong); staining area scores were 0 (none), 1 (1-25%), 2 (26-50%), 3 (51-75%), and 4 (76-100%).…”

Section: Immunohistochemistry (Ihc)mentioning

confidence: 99%

“…2c and d). As described previously, AGS cells showed low expression of MUS81 [26]. We further constructed the MUS81 wild-type (MUS81-WT) plasmid and transfected it into AGS cells (oeMUS81-WT), whereas the control group was transfected with the vector plasmid (oeVector).…”

Section: Mus81 Regulates β-Trcp-mediated Wee1 Ubiquitinationmentioning

confidence: 99%

“…In malignant diseases, its expression level and biological function differ depending on the tumor type [24,25]. Our previous study demonstrated that MUS81 was overexpressed and it promoted tumor metastasis by regulating the expression of the epithelialmesenchymal transition (EMT) marker ZEB1 in gastric cancer [26]; however, its therapeutic value as a predictive target needs to be further studied in gastric cancer.…”

Section: Introductionmentioning

confidence: 99%

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Targeting MUS81 promotes the anticancer effect of WEE1 inhibitor and immune checkpoint blocking combination therapy via activating cGAS/STING signaling in gastric cancer cells

Shen

Zhang

et al. 2021

J Exp Clin Cancer Res

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Background Identification of genomic biomarkers to predict the anticancer effects of indicated drugs is considered a promising strategy for the development of precision medicine. DNA endonuclease MUS81 plays a pivotal role in various biological processes during malignant diseases, mainly in DNA damage repair and replication fork stability. Our previous study reported that MUS81 was highly expressed and linked to tumor metastasis in gastric cancer; however, its therapeutic value has not been fully elucidated. Methods Bioinformatics analysis was used to define MUS81-related differential genes, which were further validated in clinical tissue samples. Gain or loss of function MUS81 cell models were constructed to elucidate the effect and mechanism of MUS81 on WEE1 expression. Moreover, the antitumor effect of targeting MUS81 combined with WEE1 inhibitors was verified using in vivo and in vitro assays. Thereafter, the cGAS/STING pathway was evaluated, and the therapeutic value of MUS81 for immunotherapy of gastric cancer was determined. Results In this study, MUS81 negatively correlated with the expression of cell cycle checkpoint kinase WEE1. Furthermore, we identified that MUS81 regulated the ubiquitination of WEE1 via E-3 ligase β-TRCP in an enzymatic manner. In addition, MUS81 inhibition could sensitize the anticancer effect of the WEE1 inhibitor MK1775 in gastric cancer in vitro and in vivo. Interestingly, when MUS81 was targeted, it increased the accumulation of cytosolic DNA induced by MK1775 treatment and activated the DNA sensor STING-mediated innate immunity in the gastric cancer cells. Thus, the WEE1 inhibitor MK1775 specifically enhanced the anticancer effect of immune checkpoint blockade therapy in MUS81 deficient gastric cancer cells. Conclusions Our data provide rational evidence that targeting MUS81 could elevate the expression of WEE1 by regulating its ubiquitination and could activate the innate immune response, thereby enhancing the anticancer efficacy of WEE1 inhibitor and immune checkpoint blockade combination therapy in gastric cancer cells.

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The DNA Endonuclease Mus81 Regulates ZEB1 Expression and Serves as a Target of BET4 Inhibitors in Gastric Cancer

Cited by 15 publications

References 45 publications

ZEB1: A Critical Regulator of Cell Plasticity, DNA Damage Response, and Therapy Resistance

ZEB1: A Critical Regulator of Cell Plasticity, DNA Damage Response, and Therapy Resistance

Resolvases, Dissolvases, and Helicases in Homologous Recombination: Clearing the Road for Chromosome Segregation

Targeting MUS81 promotes the anticancer effect of WEE1 inhibitor and immune checkpoint blocking combination therapy via activating cGAS/STING signaling in gastric cancer cells

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