Genome-wide CRISPR-Cas9 screen identified KLF11 as a druggable suppressor for sarcoma cancer stem cells

Wang, Yicun; Wu, Jinhui; Chen, Hui; Yang, Yang; Xiao, Chengwu; Yi, Xiaoming; Shi, Changjie; Zhong, Ke; He, Haowei; Li, Yaoming; Wu, Zhenjie; Zhou, Guangxin; Rao, Qiu; Wang, Xiaoxia; Zhou, Xianghui; Lomberk, Gwen; Liu, Bing; Zhao, Jianning; Ge, Jingping; Zhou, Wenzong; Chen, Xiaoyuan; Chen, Cheng; Zhou, Xuhui; Wang, Linhui; Guan, Kun‐Liang; Qu, Le

doi:10.1126/sciadv.abe3445

Cited by 28 publications

(18 citation statements)

References 55 publications

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“…Overexpression of transglutaminase‐2 increases the stemness of OSCs, thereby increasing migration and invasiveness (Fuja et al, 2018). There are other genes that change the metastatic ability of osteosarcoma by changing the stemness of OSCs (Han et al, 2020; Jiang et al, 2017; Qu et al, 2018; Y. Wang et al, 2021; Yao et al, 2020; Zhao et al, 2019).…”

Section: Genes Related To Oscsmentioning

confidence: 99%

“…In addition, genes can also regulate the metastasis of osteosarcoma cells by changing the stemness of OSCs. KLF11 inhibits the metastasis of sarcoma stem cells by inhibiting the expression of YAP (Y. Wang et al, 2021). Long non‐coding RNA DANCR increases the stemness of OSCs and promotes the metastasis of OSCs by upregulating AXL through competitive binding to miR‐33a‐5p (Jiang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Advances in the research of osteosarcoma stem cells and its related genes

Zhang

Wei

Weng

et al. 2022

Cell Biology International

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Osteosarcoma is a malignant tumor that often occurs in adolescents. There is an urgent need for new treatment options for osteosarcoma due to its poor prognosis after metastasis. Cancer stem cell (CSC) theory states that CSCs represent a small proportion of cancer cells. These CSC have self‐renewal ability and are closely associated with cancer growth and metastasis as well as chemotherapy resistance. Similarly, osteosarcoma stem cells (OSCs) play an important role in the growth, metastasis, and chemotherapy resistance of osteosarcoma cells. Targeting OSCs may represent a future treatment of osteosarcoma. Furthermore, some genes have been shown to regulate the growth, metastasis, and chemotherapy resistance of osteosarcoma cells by altering the stemness of OSCs. Targeting these genes may help in the treatment of osteosarcoma. This review mainly discusses recent advances in the research of OSCs and their related genes.

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Section: Genes Related To Oscsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Advances in the research of osteosarcoma stem cells and its related genes

Zhang

Wei

Weng

et al. 2022

Cell Biology International

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“…KLF8 and KLF11 have also been shown to be involved in OS cancer stem cell induction [ 185 , 186 ]. KLF8 is highly expressed in OS tissues and highly enriched in CD133-positive cancer stem cell populations [ 185 ].…”

Section: Role Of Klfs In Osteoarthritis Osteoporosis and Osteosarcomamentioning

confidence: 99%

“…KLF11 has previously been shown to play a crucial negative role in cancer stem cells in non-OS tumors [ 190 ]. Through genome-wide screening, Wang et al recently identified KLF11 as a top-hit suppressor molecule in OS cancer stem cell induction [ 186 ]. Mechanistically, KLF11 was associated with yes-associated protein (YAP)/TEA domain family member 1 (TEAD) at adjacent DNA sites, where KLF11 suppressed YAP/TEAD functions by recruiting the SIN3 transcription regulator family member A (SIN3A)/histone deacetylase (HDAC) repressor complex [ 186 ].…”

Section: Role Of Klfs In Osteoarthritis Osteoporosis and Osteosarcomamentioning

confidence: 99%

Kruppel-like Factors in Skeletal Physiology and Pathologies

Abe

Saeki

Ikeda

et al. 2022

IJMS

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Kruppel-like factors (KLFs) belong to a large group of zinc finger-containing transcription factors with amino acid sequences resembling the Drosophila gap gene Krüppel. Since the first report of molecular cloning of the KLF family gene, the number of KLFs has increased rapidly. Currently, 17 murine and human KLFs are known to play crucial roles in the regulation of transcription, cell proliferation, cellular differentiation, stem cell maintenance, and tissue and organ pathogenesis. Recent evidence has shown that many KLF family molecules affect skeletal cells and regulate their differentiation and function. This review summarizes the current understanding of the unique roles of each KLF in skeletal cells during normal development and skeletal pathologies.

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“…Compared with previous functional deletion screening systems, the CRISPR/Cas9 screening system has higher sensitivity, higher data reproducibility and minimal off-target effects. In recent years, CRISPR/Cas9 library screening has been used in various models to identify genes that are critical for cancer cell survival, proliferation, migration, and drug resistance [ 10 – 13 ].…”

Section: Introductionmentioning

confidence: 99%

Genome-wide CRISPR screen identified Rad18 as a determinant of doxorubicin sensitivity in osteosarcoma

Liu

et al. 2022

J Exp Clin Cancer Res

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Background Osteosarcoma (OS) is a malignant bone tumor mostly occurring in children and adolescents, while chemotherapy resistance often develops and the mechanisms involved remain challenging to be fully investigated. Methods Genome-wide CRISPR screening combined with transcriptomic sequencing were used to identify the critical genes of doxorubicin resistance. Analysis of clinical samples and datasets, and in vitro and in vivo experiments (including CCK-8, apoptosis, western blot, qRT-PCR and mouse models) were applied to confirm the function of these genes. The bioinformatics and IP-MS assays were utilized to further verify the downstream pathway. RGD peptide-directed and exosome-delivered siRNA were developed for the novel therapy strategy. Results We identified that E3 ubiquitin-protein ligase Rad18 (Rad18) contributed to doxorubicin-resistance in OS. Further exploration revealed that Rad18 interact with meiotic recombination 11 (MRE11) to promote the formation of the MRE11-RAD50-NBS1 (MRN) complex, facilitating the activation of the homologous recombination (HR) pathway, which ultimately mediated DNA damage tolerance and leaded to a poor prognosis and chemotherapy response in patients with OS. Rad18-knockout effectively restored the chemotherapy response in vitro and in vivo. Also, RGD-exosome loading chemically modified siRad18 combined with doxorubicin, where exosome and chemical modification guaranteed the stability of siRad18 and the RGD peptide provided prominent targetability, had significantly improved antitumor activity of doxorubicin. Conclusions Collectively, our study identifies Rad18 as a driver of OS doxorubicin resistance that promotes the HR pathway and indicates that targeting Rad18 is an effective approach to overcome chemotherapy resistance in OS.

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Genome-wide CRISPR-Cas9 screen identified KLF11 as a druggable suppressor for sarcoma cancer stem cells

Cited by 28 publications

References 55 publications

Advances in the research of osteosarcoma stem cells and its related genes

Advances in the research of osteosarcoma stem cells and its related genes

Kruppel-like Factors in Skeletal Physiology and Pathologies

Genome-wide CRISPR screen identified Rad18 as a determinant of doxorubicin sensitivity in osteosarcoma

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