In vivo CRISPR screening unveils histone demethylase UTX as an important epigenetic regulator in lung tumorigenesis

Wu, Qibiao; Tian, Ye; Zhang, Jian; Tong, Xinyuan; Huang, Hsin‐Yi; Li, Shuai; Zhao, Hong; Tang, Ying; Yuan, Chongze; Wang, Kun; Fang, Zhaoyuan; Gao, Lei; Hu, Xin; Li, Fuming; Qin, Zhen; Yao, Shun; Chen, Ting; Chen, Haiquan; Zhang, Gong; Liu, Wanting; Sun, Yihua; Chen, Luonan; Wong, Kwok-Kin; Ge, Kai; Chen, Liang; Ji, Hongbin

doi:10.1073/pnas.1716589115

Cited by 81 publications

(85 citation statements)

References 50 publications

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“…6 Examples include UC, 49 lung cancer, 58 pancreatic squamous carcinoma, 32 multiple myeloma, 59 and some breast cancer cell lines. In several cancer types, inhibitors of the EZH2 methyltransferase like GSK126 are more efficacious in cell lines and mouse models with UTX loss of function.…”

Section: Clinical Applicationsmentioning

confidence: 99%

“…In several cancer types, inhibitors of the EZH2 methyltransferase like GSK126 are more efficacious in cell lines and mouse models with UTX loss of function. 6 Examples include UC, 49 lung cancer, 58 pancreatic squamous carcinoma, 32 multiple myeloma, 59 and some breast cancer cell lines. 60 Conversely, inhibitors targeting the UTX JmjC domain could be employed in cancers that require its demethylase function.…”

Section: Clinical Applicationsmentioning

confidence: 99%

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The histone demethylase UTX/KDM6A in cancer: Progress and puzzles

Schulz

Lang

Koch

et al. 2019

Intl Journal of Cancer

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The lysine‐specific demethylase 6A/UTX (gene name KDM6A) acts as a component of the COMPASS complex to control gene activation. UTX demethylates H3K27me2/3 at genes and enhancers. Deleterious mutations in KDM6A are found in many cancer types, prominently urothelial carcinoma and certain T‐cell leukemias. In certain cancers, however, UTX supports oncogenic transcription factors, e.g. steroid hormone receptors in breast and prostate cancer. In fetal development, UTX regulates lineage choice and cell differentiation. Analogously, loss of UTX function in cancer may lead to metaplasia or impede differentiation. Likely because its function is contingent on its interacting transcription factors, the effects of UTX inactivation are not uniform and require detailed investigation in each cancer type. In urothelial carcinoma, in particular, the functional consequences of the frequent mutations in KDM6A and other COMPASS component genes are poorly understood. Nevertheless, UTX inactivation appears to sensitize many cancers to inhibitors of the H3K27 methyltransferase EZH2. Conversely, inhibitors of UTX enzymatic activity may be applicable in cancers with an oncogenic UTX function. Intriguingly, the fact that KDM6A is localized on the X‐chromosome, but both copies are expressed, may account for gender‐specific differences in cancer susceptibility. In conclusion, despite recent progress, many open questions need to be addressed, most importantly, the detailed mechanisms by which KDM6A inactivation promotes various cancers, but also with which proteins UTX interacts in and apart from the COMPASS complex, and to which extent its catalytic function is required for its tumor‐suppressive function.

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Section: Clinical Applicationsmentioning

confidence: 99%

Section: Clinical Applicationsmentioning

confidence: 99%

The histone demethylase UTX/KDM6A in cancer: Progress and puzzles

Schulz

Lang

Koch

et al. 2019

Intl Journal of Cancer

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“…The results of this study showed that BIS knockout by CRISPR/Cas9 led to the inhibition of migration and invasion of A549 cells. Also, CRISPR/Cas9 has revealed the role of other transcription factors such as: UTX and Rsf-1 in lung tumorigenesis and drug sensitivity, respectively (40,41). Hence, CRISPR/Cas9 is an effi cient system for discovering the role of genes in lung cancer.…”

Section: Discussionmentioning

confidence: 99%

ZEB1 and ZEB2 gene editing mediated by CRISPR/Cas9 in A549 cell line

Mohammadinejad¹,

Sassan²,

Pardakhty³

et al. 2020

BLL

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OBJECTIVES: One of the best approaches for recognition of protein function is the induction of mutations for a gene knockout. In line with this strategy, gene editing tools allow researchers to induce these mutations. Lung cancer is one of the leading causes of death worldwide. ZEB1 and ZEB2 genes are the candidates for this disease. METHODS: The ZEB1 and ZEB2 knockout in the non-small cell lung cancer cell line (A549 cell) was investigated. Purifi cation of recombination plasmids was performed from bacteria and then was transported to the A549 cell line. The deletion of ZEB1 and ZEB2 were examined by PCR. RESULTS: The results demonstrated the mutation and deletion in ZEB1 and ZEB2 genes. Based on the fi ndings of this study, A549 cells were transfected with the vectors carrying the sgRNA/Cas9, simultaneously. The DNA fragment demonstrated the presence of indels in target sites as well as provided the potential of CRISPR/Cas9 system. CONCLUSION: CRISPR/Cas9 offers a great potential as an effi cient technique for editing of ZEB1 and ZEB2 genes in A549 cell line (Tab. 1, Fig. 6, Ref.

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“…Ad-Cre (adenovirus) virus (OBIO) was inoculated (1 × 10 9 per mouse) using the intranasal/orthotropic infection protocol as described. 17 Eight weeks later, the lungs were harvested, and western blot analysis was carried out.…”

Section: Lung Cancer Mouse Modelmentioning

confidence: 99%

ZNF251 promotes the progression of lung cancer by activating ERK signaling

et al. 2020

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Aberrant activation of ERK signaling is a hallmark of lung cancer. Although constitutively activating mutations of EGFR and KRAS contribute to the hyperactivation of ERK1/2, other mechanisms remain elusive. In this study, the zinc finger protein ZNF251 was found to be upregulated in clinical lung cancer samples, and it promoted the growth of lung cancer cells and the growth of primary lung KPC cells from mouse models (Ad‐Cre, KrasG12D, and P53f/f). In studying the molecular mechanism, ZNF251 was found to inhibit the expression of dual‐specificity phosphatase 6, a negative regulator of ERK activation, by directly binding to its promoter region. Taken together, our data indicate the tumor‐promoting effects of ZNF251 in lung cancer and suggest that ZNF251 is a therapeutic target.

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In vivo CRISPR screening unveils histone demethylase UTX as an important epigenetic regulator in lung tumorigenesis

Cited by 81 publications

References 50 publications

The histone demethylase UTX/KDM6A in cancer: Progress and puzzles

The histone demethylase UTX/KDM6A in cancer: Progress and puzzles

ZEB1 and ZEB2 gene editing mediated by CRISPR/Cas9 in A549 cell line

ZNF251 promotes the progression of lung cancer by activating ERK signaling

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