LncRNA CRNDE Promotes ATG4B-Mediated Autophagy and Alleviates the Sensitivity of Sorafenib in Hepatocellular Carcinoma Cells

Chen, Lingxi; Sun, Liangbo; Dai, Xufang; Li, Tao; Yan, Xiaojing; Zhang, Yueting; Xiao, Hanxi; Shen, Xiaodong; Huang, Gang; Xiang, Wei; Zhang, Yan; Tan, Dehong; Yang, Shi‐Ming; Nie, Yongzhan; Huang, Xuequan; Lian, Jiqin; He, Fengtian

doi:10.3389/fcell.2021.687524

Cited by 17 publications

(12 citation statements)

References 49 publications

(63 reference statements)

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“…The mechanisms underlying sorafenib resistance remain to be established. Here, we have demonstrated an oncogenic role of CRNDE in sorafenib resistance of HCC, consistent with previous reports [ 13 ]. In our experiments, CRNDE was upregulated in HCC tumor specimens and induced elevation of EGFR expression, thereby increasing proliferation and sorafenib resistance.…”

Section: Discussionsupporting

confidence: 93%

“…CRNDE has been shown to act as an oncogene promoting tumor proliferation, invasion, migration, and drug resistance in multiple cancer types, including HCC [ 9 – 12 ]. A recent study showed that CRNDE induces sorafenib resistance in HCC by triggering autophagy via upregulation of ATG4B [ 13 ]. Additionally, CRNDE is reported to inhibit CELF2 and LATS2 expression and promote HCC proliferation, migration, and chemoresistance through epigenetic interactions with EZH2, a key component of the PRC2 complex.…”

Section: Introductionmentioning

confidence: 99%

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CRNDE acts as an epigenetic modulator of the p300/YY1 complex to promote HCC progression and therapeutic resistance

et al. 2022

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Background Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies worldwide. The long-term prognosis for HCC remains extremely poor, with drug resistance being the major underlying cause of recurrence and mortality. The lncRNA colorectal neoplasia differentially expressed (CRNDE) is an epigenetic mediator and plays an important role to drive proliferation and drug resistance in HCC. However, CRNDE as an epigenetic regulator with influences sorafenib resistance in HCC is unclear. Thus, we explore the potential of targeting the CRNDE/p300/YY1 axis as a novel therapeutic strategy to overcome sorafenib resistance of HCC. Method Detection of the expression level of CRNDE and EGFR in clinical specimens of HCC. CRNDE, EGFR, p300, and YY1expression were altered in HCC cells through transfection with different plasmids, and cell proliferation, migration, invasion, and sorafenib resistance were subsequently observed. Immunoprecipitation, chromatin immunoprecipitation, re-chromatin immunoprecipitation, site-directed mutagenesis, RNA Immunoprecipitation, immune fluorescence, qRT-PCR, and western blotting were performed to uncover the mechanisms of CRNDE regulation. The xenograft nude mice model was used to investigate the tumor growth and sorafenib resistance. Results In this study, we showed that CRNDE expression is significantly positively correlated with that of epidermal growth factor receptor (EGFR) in clinical specimens of HCC and induces proliferation and sorafenib resistance of HCC via EGFR-mediated signaling. Mechanistically, CRNDE stabilized the p300/YY1 complex at the EGFR promoter and simultaneously enhanced histone H3K9 and H3K27 acetylation, which serve as markers of relaxed chromatin. EGFR was positively upregulated by the epigenetic complex, p300/YY1, in a manner dependent on CRNDE expression, leading to enhanced tumor cell proliferation and sorafenib resistance. Furthermore, C646, a p300 inhibitor, suppressed EGFR transcriptional activity by decreasing chromatin relaxation and YY1 binding, which effectively reduced proliferation/sorafenib resistance and prolonged overall survival. Conclusion Our collective findings support the potential of targeting the CRNDE/p300/YY1 axis as a novel therapeutic strategy to overcome sorafenib resistance of HCC.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

CRNDE acts as an epigenetic modulator of the p300/YY1 complex to promote HCC progression and therapeutic resistance

et al. 2022

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“…In addition, CRNDE is involved in the initiation and tumorigenesis of several cancers. For example, it promotes atg4b-mediated autophagy and attenuates sorafenib sensitivity in hepatocellular carcinoma cells ( Chen et al, 2021 ); it regulates eIF4A3/MUC1/EGFR signalling and modulates the response of EGFR-mutant lung cancer to EGFR tyrosine kinase inhibitor resistance ( Takahashi et al, 2021 ). In addition, CRNDE expression is modulated via DNA methylation, and CRNDE exhibits protective effects on CLL by preventing CLL progression through the miR-28/NDRG2 axis ( Ni et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Modification Patterns of DNA Methylation-Related lncRNAs Regulating Genomic Instability for Improving the Clinical Outcomes and Tumour Microenvironment Characterisation of Lower-Grade Gliomas

Maimaiti

Aili

Turhon

et al. 2022

Front. Mol. Biosci.

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Background: DNA methylation is an important epigenetic modification that affects genomic instability and regulates gene expression. Long non-coding RNAs (lncRNAs) modulate gene expression by interacting with chromosomal modifications or remodelling factors. It is urgently needed to evaluate the effects of DNA methylation-related lncRNAs (DMlncRNAs) on genome instability and further investigate the mechanism of action of DMlncRNAs in mediating the progression of lower-grade gliomas (LGGs) and their impact on the immune microenvironment.Methods: LGG transcriptome data, somatic mutation profiles and clinical features analysed in the present study were obtained from the CGGA, GEO and TCGA databases. Univariate, multivariate Cox and Lasso regression analyses were performed to establish a DMlncRNA signature. The KEGG and GO analyses were performed to screen for pathways and biological functions associated with key genes. The ESTIMATE and CIBERSORT algorithms were used to determine the level of immune cells in LGGs and the immune microenvironment fraction. In addition, DMlncRNAs were assessed using survival analysis, ROC curves, correlation analysis, external validation, independent prognostic analysis, clinical stratification analysis and qRT-PCR.Results: We identified five DMlncRNAs with prognostic value for LGGs and established a prognostic signature using them. The Kaplan–Meier analysis revealed 10-years survival rate of 10.10% [95% confidence interval (CI): 3.27–31.40%] in high-risk patients and 57.28% (95% CI: 43.17–76.00%) in low-risk patients. The hazard ratio (HR) and 95% CI of risk scores were 1.013 and 1.009–1.017 (p < 0.001), respectively, based on the univariate Cox regression analysis and 1.009 and 1.004–1.013 (p < 0.001), respectively, based on the multivariate Cox regression analysis. Therefore, the five-lncRNAs were identified as independent prognostic markers for patients with LGGs. Furthermore, GO and KEGG analyses revealed that these lncRNAs are involved in the prognosis and tumorigenesis of LGGs by regulating cancer pathways and DNA methylation.Conclusion: The findings of the study provide key information regarding the functions of lncRNAs in DNA methylation and reveal that DNA methylation can regulate tumour progression through modulation of the immune microenvironment and genomic instability. The identified prognostic lncRNAs have high potential for clinical grouping of patients with LGGs to ensure effective treatment and management.

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“…In addition, Chen et al found that CRNDE triggered autophagy in HepG2 and Hep3B cells by increasing ATG4B levels via sponging miR-543. CRNDE silencing enhanced the sorafenib sensitivity of HepG2 and Hep3B cells, indicating that CRNDE may promote sorafenib resistance in HCC by driving ATG4B-mediated autophagy (193). Highmobility group box 1 (HMGB1) is a classical non-histone protein closely associated with autophagy (194).…”

Section: Lncrnas Control the Cellular Death Pathways In Cancer Drug R...mentioning

confidence: 99%

Non-coding RNA in cancer drug resistance: Underlying mechanisms and clinical applications

Zhou

Jia

et al. 2022

Front. Oncol.

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Cancer is one of the most frequently diagnosed malignant diseases worldwide, posing a serious, long-term threat to patients’ health and life. Systemic chemotherapy remains the first-line therapeutic approach for recurrent or metastatic cancer patients after surgery, with the potential to effectively extend patient survival. However, the development of drug resistance seriously limits the clinical efficiency of chemotherapy and ultimately results in treatment failure and patient death. A large number of studies have shown that non-coding RNAs (ncRNAs), particularly microRNAs, long non-coding RNAs, and circular RNAs, are widely involved in the regulation of cancer drug resistance. Their dysregulation contributes to the development of cancer drug resistance by modulating the expression of specific target genes involved in cellular apoptosis, autophagy, drug efflux, epithelial-to-mesenchymal transition (EMT), and cancer stem cells (CSCs). Moreover, some ncRNAs also possess great potential as efficient, specific biomarkers in diagnosis and prognosis as well as therapeutic targets in cancer patients. In this review, we summarize the recent findings on the emerging role and underlying mechanisms of ncRNAs involved in cancer drug resistance and focus on their clinical applications as biomarkers and therapeutic targets in cancer treatment. This information will be of great benefit to early diagnosis and prognostic assessments of cancer as well as the development of ncRNA-based therapeutic strategies for cancer patients.

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LncRNA CRNDE Promotes ATG4B-Mediated Autophagy and Alleviates the Sensitivity of Sorafenib in Hepatocellular Carcinoma Cells

Cited by 17 publications

References 49 publications

CRNDE acts as an epigenetic modulator of the p300/YY1 complex to promote HCC progression and therapeutic resistance

CRNDE acts as an epigenetic modulator of the p300/YY1 complex to promote HCC progression and therapeutic resistance

Modification Patterns of DNA Methylation-Related lncRNAs Regulating Genomic Instability for Improving the Clinical Outcomes and Tumour Microenvironment Characterisation of Lower-Grade Gliomas

Non-coding RNA in cancer drug resistance: Underlying mechanisms and clinical applications

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