Targeting Super-Enhancer–Associated Oncogenes in Osteosarcoma with THZ2, a Covalent CDK7 Inhibitor

Zhang, Jiajun; Liu, Weihai; Zou, Changye; Zhao, Zhiqiang; Lai, Yuanying; Shi, Zhi; Xie, Xianbiao; Huang, Gang; Wang, Yongqian; Zhang, Xuelin; Zhang, Fan; Qiao, Shan; Yin, Junqiang; Shen, Jingnan

doi:10.1158/1078-0432.ccr-19-1418

Cited by 47 publications

(43 citation statements)

References 53 publications

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“…We found that super enhancer plays an important role in the occurrence and development of osteosarcoma [40] . Further screening and sequencing results showed that gls1 gene associated with super enhancer may play an important role.…”

Section: Introductionmentioning

confidence: 79%

GLS1 Promotes The Malignant Progression of Osteosarcoma

Zeng¹,

Peng

Yin³

et al. 2021

Preprint

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Background: Osteosarcoma (OS) is the most frequent and high-grade young malignant bone tumor. The prognosis is still poor despite the use of combined therapy involving maximal surgical resection, radiotherapy and chemotherapy. Metabolic reprogramming currently is recognized as one of the hallmarks of cancer. Glutaminase 1(GLS1) has been associated with progression of tumor cell through CDK4 signaling pathway.Methods: In the study, Western blot was used to detect the expression of GLS1 protein in tumor and adjacent normal tissues of osteosarcoma patients, and Western blot was used to detect the expression of GLS1 protein in osteosarcoma cell lines. GLS1 siRNA was transfected into osteosarcoma U2OS cells. Western blot was used to detect the expression of GLS1 protein. MTT and clone formation assay were used to detect cell proliferation. Transwell chamber assay was used to detect migration and invasion. Western blot was used to detect the expression of CDK4 protein in GLS1 knockdown U2OS cells. CB-839 was used to treat U2OS cells. The IC50 value of CB-839 was detected by MTT. The proliferation and migration of CB-839 were detected by clone formation, scratch test, RNA seq sequencing, q-PCR and Western blot.Results: (1) GLS1 was highly expressed in osteosarcoma tissues and cell lines; (2) After transfection, compared with the control group, GLS1 protein expression and CDK4 protein expression of U2OS cells in the knockdown group were significantly down regulated. In vitro experiments showed that the proliferation, migration and invasion of U2OS cells were significantly down regulated; (3) CB-839 promoted apoptosis and inhibited the proliferation and migration of osteosarcoma cells by acting on upstream transcription factors EGR1 and FOXO1. Conclusion: GLS1 can promote the proliferation, migration and invasion of osteosarcoma cells by affecting the cell cycle of CDK4 signaling pathway, and can be used as a potential prognostic indicator and therapeutic target for osteosarcoma patients.

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Section: Introductionmentioning

confidence: 79%

GLS1 Promotes The Malignant Progression of Osteosarcoma

Zeng¹,

Peng

Yin³

et al. 2021

Preprint

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“…Chen et al (2018) have experimentally demonstrated that SE-inhibitors are promising small-molecule drugs for patients with osteosarcoma by targeting the MYC signaling pathway in osteosarcoma. Zhang et al (2020) found THZ2 can target SE-associated oncogenes in osteosarcoma. Using ChIP-Seq, they found that SEs are associated with oncogenic genes in osteosarcoma cells.…”

Section: Ses In Osteosarcomamentioning

confidence: 98%

“… Zhang et al (2020) found THZ2 can target SE-associated oncogenes in osteosarcoma. Using ChIP-Seq, they found that SEs are associated with oncogenic genes in osteosarcoma cells.…”

Section: Ses In Bone-related Diseasesmentioning

confidence: 98%

“…Compared with THZ1, THZ2 is a newly developed CDK7 inhibitor with a fivefold increase of half-life. Zhang et al (2020) found that THZ2 can impede the proliferation and metastasis of osteosarcoma via targeting SE-associated oncogenes. Overall, CDK7 inhibition is another promising target treatment therapy for bone-related diseases.…”

Section: Cdk Inhibitors Targeting Sesmentioning

confidence: 99%

“…However, the pathogenic mechanisms of many other complex diseases remain unclear, such as osteosarcoma, Ewing sarcoma, and other bone-related diseases with poor prognosis. Multiple studies have reported novel insights of which many include SEs-associated genes such as MYC ( Loven et al, 2013 ; Zhang et al, 2020 ) LIF, ( Lu et al, 2020 ), and EWS-FLI1 ( Jacques et al, 2016 ), and SEs-inhibitors with therapeutic effects such as JQ1 ( Loven et al, 2013 ; Lee et al, 2015 ; Jiang et al, 2017 ; Chen et al, 2018 ), THZ1 ( Chen et al, 2018 ; Sharifnia et al, 2019 ), and THZ2 ( Zhang et al, 2020 ) on diseases like osteosarcoma, Ewing sarcoma, MM, chordoma, and osteoarthritis. However, for osteoporosis, cartilage dysplasia, and RA, only a few therapeutic drugs have been reported that can efficiently target SEs or SEs-associated genes.…”

Section: Summary and Perspectivementioning

confidence: 99%

See 2 more Smart Citations

Functions and Clinical Significance of Super-Enhancers in Bone-Related Diseases

Ouyang

et al. 2020

Front. Cell Dev. Biol.

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Super-enhancers (SEs) are a large cluster of cis-regulatory DNA elements that contain many binding motifs, which master transcription factors and cofactors bind to with high density. SEs usually regulate the expression of genes that can control the cell identity and fate, and SEs can be used to explain the patterns of the expression of cell-specific genes. Hence, it shows great potential for application in the treatment of diseases like cancer. At present, the clinical treatments for osteosarcoma, Ewing sarcoma, and other bone-related diseases remain challenging. The poor prognosis and difficult treatment of these diseases imposes heavy economic burden on patients and society. In recent years, research on SEs with respect to bone-related diseases has attracted increasing attention. In this paper, we first review the identification and functional mechanisms of SEs. Then, we integrate the findings of the emerging studies on SEs in bone-related diseases. Finally, we summarize recent strategies for targeting SEs for the treatment of bone-related diseases. This review aims to provide comprehensive insights into the roles of SEs in bone-related diseases.

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SNPs Give LACTB Oncogene‐Like Functions and Prompt Tumor Progression via Dual‐Regulating p53

Huang,

Zhang,

et al. 2024

Advanced Science

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LACTB is identified as a tumor suppressor in several tumors. However, preliminary study reveals that LACTB is overexpressed in osteosarcoma and indicates poor prognosis. Two missense mutations (rs34317102 and rs2729835) exist simultaneously in 92.31% of osteosarcoma patients and cause M5L and R469K double mutations in LACTB, suggesting the biologic function of LACTB protein may be altered in osteosarcoma. Moreover, LACTBM5L+R469K overexpression can promote malignant progression in different tumors, which suggests that the M5L and R469K mutations confer oncogene‐like functions to LACTB. Mechanistically, LACTBM5L+R469K not only reduces the wild type p53 via enhancing PSMB7 catalytic activity, but also protects p53R156P protein from lysosomal degradation, which suggesting LACTBM5L+R469K is a dual‐regulator for wt‐p53 and mutant p53, and derive oncogene‐like functions. More importantly, clavulanate potassium, a bacterial β‐lactamase inhibitor, can inhibit osteosarcoma proliferation and sensitize osteosarcoma to cisplatin by binding and blocking LACTBM5L+R469K. These findings revealed that the M5L and R469K double mutations can diminish the tumor suppressive ability of wild type LACTB and provide oncogene‐like functions to LACTB. Inhibiting LACTBM5L+R469K can suppress the progression of osteosarcoma harbouring wild‐type or mutant p53. Clavulanate potassium is a promising drug by targeting LACTBM5L+R469K‐p53 pathway for the treatment of osteosarcoma patients.

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Targeting Super-Enhancer–Associated Oncogenes in Osteosarcoma with THZ2, a Covalent CDK7 Inhibitor

Cited by 47 publications

References 53 publications

GLS1 Promotes The Malignant Progression of Osteosarcoma

GLS1 Promotes The Malignant Progression of Osteosarcoma

Functions and Clinical Significance of Super-Enhancers in Bone-Related Diseases

SNPs Give LACTB Oncogene‐Like Functions and Prompt Tumor Progression via Dual‐Regulating p53

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