Compound AC1Q3QWB upregulates CDKN1A and SOX17 by interrupting the HOTAIR—EZH2 interaction and enhances the efficacy of tazemetostat in endometrial cancer

Chen, Lingli; Zheng, Xingyu; Liu, Wenlu; Sun, Yiqing; Zhao, Shuangshuang; Tian, Lina; Tian, Wenyan; Xue, Fengxia; Kang, Chunsheng; Wang, Yingmei

doi:10.1016/j.canlet.2023.216445

Cited by 8 publications

(3 citation statements)

References 78 publications

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“…To restore ERBIN expression in MES-GBM, we focus on the interaction between HOTAIR and EZH2 as a research breakthrough that has been extensively studied 53 , 54 . In our previous study, ADQ and AQB were identified as small-molecule inhibitors capable of blocking the HOTAIR-EZH2 interaction, showing positive preclinical effects in GBM and other cancer models 41 , 55 , 56 . EPIC-0412 was then designed and screened to further sensitize GBM cells to TMZ by blocking the HOTAIR-EZH2 interaction 32 .…”

Section: Discussionmentioning

confidence: 99%

CRISPR-Cas9 library screening combined with an exosome-targeted delivery system addresses tumorigenesis/TMZ resistance in the mesenchymal subtype of glioblastoma

Zhao,

Cui,

Zhan

et al. 2024

Theranostics

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Rationale: The large-scale genomic analysis classifies glioblastoma (GBM) into three major subtypes, including classical (CL), proneural (PN), and mesenchymal (MES) subtypes. Each of these subtypes exhibits a varying degree of sensitivity to the temozolomide (TMZ) treatment, while the prognosis corresponds to the molecular and genetic characteristics of the tumor cell type. Tumors with MES features are predominantly characterized by the NF1 deletion/alteration, leading to sustained activation of the RAS and PI3K-AKT signaling pathways in GBM and tend to acquire drug resistance, resulting in the worst prognosis compared to other subtypes (PN and CL). Here, we used the CRISPR/Cas9 library screening technique to detect TMZ-related gene targets that might play roles in acquiring drug resistance, using overexpressed KRAS-G12C mutant GBM cell lines. The study identified a key therapeutic strategy to address the chemoresistance against the MES subtype of GBM. Methods: The CRISPR-Cas9 library screening was used to discover genes associated with TMZ resistance in the U87-KRAS (U87-MG which is overexpressed KRAS-G12C mutant) cells. The patient-derived GBM primary cell line TBD0220 was used for experimental validations in vivo and in vitro. Chromatin isolation by RNA purification (ChIRP) and chromatin immunoprecipitation (ChIP) assays were used to elucidate the silencing mechanism of tumor suppressor genes in the MES-GBM subtype. The small-molecule inhibitor EPIC-0412 was obtained through high-throughput screening. Transmission electron microscopy (TEM) was used to characterize the exosomes (Exos) secreted by GBM cells after TMZ treatment. Blood-derived Exos-based targeted delivery of siRNA, TMZ, and EPIC-0412 was optimized to tailor personalized therapy in vivo. Results: Using the genome-wide CRISPR-Cas9 library screening, we found that the ERBIN gene could be epigenetically regulated in the U87-KRAS cells. ERBIN overexpression inhibited the RAS signaling and downstream proliferation and invasion effects of GBM tumor cells. EPIC-0412 treatment inhibited tumor proliferation and EMT progression by upregulating the ERBIN expression both in vitro and in vivo. Genome-wide CRISPR-Cas9 screening also identified RASGRP1(Ras guanine nucleotide-releasing protein 1) and VPS28(Vacuolar protein sorting-associated protein 28) genes as synthetically lethal in response to TMZ treatment in the U87-KRAS cells. We found that RASGRP1 activated the RAS-mediated DDR pathway by promoting the RAS-GTP transformation. VPS28 promoted the Exos secretion and decreased intracellular TMZ concentration in GBM cells. The targeted Exos delivery system encapsulating drugs and siRNAs together showed a powerful therapeutic effect against GBM in vivo. Conclusions: We demonstrate a new mechanism by which ERBIN is epigenetically silenced by the RAS signaling in the MES subtype of GBM. Restoration of the ERBIN expression with EPIC-0412 significantly inhibits the RAS signali...

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Section: Discussionmentioning

confidence: 99%

CRISPR-Cas9 library screening combined with an exosome-targeted delivery system addresses tumorigenesis/TMZ resistance in the mesenchymal subtype of glioblastoma

Zhao,

Cui,

Zhan

et al. 2024

Theranostics

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“…Thus, the estrogen–HOTAIR axis is a potential target in EC therapy [ 94 ]. In other research, it was proved that HOTAIR expression was higher in G3 EC than in G1/G2 [ 95 ]. Similar actions exhibit long non-coding antisense RNA myeloid-specific 1 (HOTAIRM1).…”

Section: The Role Of Lncrna In Endometrial Cancermentioning

confidence: 99%

The Promotive and Inhibitory Role of Long Non-Coding RNAs in Endometrial Cancer Course—A Review

Jasielski,

Zawlik,

Bogaczyk

et al. 2024

Cancers

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Endometrial cancer is one of the most common malignant tumours in women. The development of this tumour is associated with several genetic disorders, many of which are still unknown. One type of RNA molecules currently being intensively studied in many types of cancer are long non-coding RNAs (lncRNAs). LncRNA-coding genes occupy a large fraction of the human genome. LncRNAs regulate many aspects of cell development, metabolism, and other physiological processes. Diverse types of lncRNA can function as a tumour suppressor or an oncogene that can alter migration, invasion, cell proliferation, apoptosis, and immune system response. Recent studies suggest that selected lncRNAs are important in an endometrial cancer course. Our article describes over 70 lncRNAs involved in the development of endometrial cancer, which were studied via in vivo and in vitro research. It was proved that lncRNAs could both promote and inhibit the development of endometrial cancer. In the future, lncRNAs may become an important therapeutic target. The aim of this study is to review the role of lncRNAs in the development of carcinoma of uterine body.

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“…In BC, circulating HOTAIR can predict early relapse ( Abdel-Hamid et al, 2023 ) and therapy response ( Lu et al, 2018 ). In GC, HOTAIR expression in serum exosomes is significantly increased and related to metastatic progression ( P. Chen L. et al, 2023 ). In liver cancer (LC), circulating HOTAIR is a potential biomarker used for hepatocellular carcinoma (HCC) detection in cirrhotic livers and prediction of tumour stage ( El-Shendidi, Ghazala and Hassouna, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

The role of HOTAIR in the modulation of resistance to anticancer therapy

Cantile,

Belli,

Scognamiglio

et al. 2024

Front. Mol. Biosci.

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Leading anti-tumour therapeutic strategies typically involve surgery and radiotherapy for locally advanced (non-metastatic) cancers, while hormone therapy, chemotherapy, and molecular targeted therapy are the current treatment options for metastatic cancer. Despite the initially high sensitivity rate to anticancer therapies, a large number of patients develop resistance, leading to a poor prognosis. The mechanisms related to drug resistance are highly complex, and long non-coding RNAs appear to play a crucial role in these processes. Among these, the lncRNA homeobox transcript antisense intergenic RNA (HOTAIR), widely implicated in cancer initiation and progression, likewise plays a significant role in anticancer drug resistance. It can modulate cell activities such as proliferation, apoptosis, hypoxia, autophagy, as well as epithelial-mesenchymal transition, thereby contributing to the development of resistant tumour cells. In this manuscript, we describe different mechanisms of antitumor drug resistance in which HOTAIR is involved and suggest its potential as a therapeutic predictive biomarker for the management of cancer patients.

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Compound AC1Q3QWB upregulates CDKN1A and SOX17 by interrupting the HOTAIR—EZH2 interaction and enhances the efficacy of tazemetostat in endometrial cancer

Cited by 8 publications

References 78 publications

CRISPR-Cas9 library screening combined with an exosome-targeted delivery system addresses tumorigenesis/TMZ resistance in the mesenchymal subtype of glioblastoma

CRISPR-Cas9 library screening combined with an exosome-targeted delivery system addresses tumorigenesis/TMZ resistance in the mesenchymal subtype of glioblastoma

The Promotive and Inhibitory Role of Long Non-Coding RNAs in Endometrial Cancer Course—A Review

The role of HOTAIR in the modulation of resistance to anticancer therapy

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