Targeting epigenetic regulators to overcome drug resistance in cancers

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Фев. 17, 2023

Abstract Drug resistance is mainly responsible for cancer recurrence and poor prognosis. Epigenetic regulation a heritable change in gene expressions independent of nucleotide sequence changes. As the common epigenetic mechanisms, DNA methylation, histone modification, non-coding RNA have been well studied. Increasing evidence has shown that aberrant regulations contribute to tumor resistance. Therefore, targeting regulators represents an effective strategy reverse drug In this review, we summarize roles addition, as essential factors modifications, demethylases mediate or genomic modifications. Herein, comprehensively describe functions demethylase family including lysine-specific family, Jumonji C-domain-containing arginine fully discuss their regulatory mechanisms related therapeutic strategies, small-molecule inhibitors small interfering overcome resistance, are also described.

Язык: Английский

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Loss of lncRNA LINC01056 leads to sorafenib resistance in HCC

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Апрель 6, 2024

Abstract Background and aims Sorafenib is a major nonsurgical option for patients with advanced hepatocellular carcinoma (HCC); however, its clinical efficacy largely undermined by the acquisition of resistance. The aim this study was to identify key lncRNA involved in regulation sorafenib response HCC. Materials methods A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) single-guide RNA (sgRNA) synergistic activation mediator (SAM)-pooled library applied screen regulated treatment. role identified mediating HCC examined vitro vivo. underlying mechanism delineated proteomic analysis. significance expression evaluated multiplex immunostaining on human microtissue array. Results CRISPR/Cas9 screening revealed that Linc01056 among most downregulated lncRNAs sorafenib-resistant cells. Knockdown reduced sensitivity cells sorafenib, suppressing apoptosis promoting tumour growth mice Proteomic analysis knockdown sorafenib-treated induced genes related fatty acid oxidation (FAO) while repressing glycolysis-associated genes, leading metabolic switch favouring higher intracellular energy production. FAO inhibition significantly restored sorafenib. Mechanistically, we determined PPARα critical molecule governing upon indeed, tumours Clinically, predicted optimal overall progression-free survival outcomes better response. indicated low level Conclusion Our as epigenetic regulator potential therapeutic target

Язык: Английский

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Histone lactylation promotes multidrug resistance in hepatocellular carcinoma by forming a positive feedback loop with PTEN

Cell Death and Disease, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 31, 2025

Язык: Английский

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Histone lactylation drives liver cancer metastasis by facilitating NSF1-mediated ferroptosis resistance after microwave ablation

Redox Biology, Год журнала: 2025, Номер 81, С. 103553 - 103553

Опубликована: Фев. 15, 2025

Язык: Английский

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Long noncoding RNA TLNC1 promotes the growth and metastasis of liver cancer via inhibition of p53 signaling

Molecular Cancer, Год журнала: 2022, Номер 21(1)

Опубликована: Апрель 27, 2022

Long non-coding RNAs (lncRNAs) have been demonstrated to play vital roles in cancer development and progression. However, their biological function mechanisms liver remain largely unknown.RNA-seq was performed with clinical hepatoma tissues paired adjacent normal identify differentially expressed lncRNAs. qPCR utilized examine the expression levels of We studied TLNC1 cell growth metastasis both mouse models. RNA-seq, RNA pull-down coupled mass spectrometry, immunoprecipitation, dual luciferase reporter assay, surface plasmon resonance analysis were used analyze functional mechanism TLNC1.Based on intersection our own TCGA survival data, identified as a potential tumorigenic lncRNA cancer. significantly enhanced cells vitro vivo. exerted its through interaction TPR inducing TPR-mediated transportation p53 from nucleus cytoplasm, thus repressing transcription target genes finally contributing progression cancer.TLNC1 is promising prognostic factor cancer, TLNC1-TPR-p53 axis can serve therapeutic for treatment.

Язык: Английский

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RNA-binding protein ZCCHC4 promotes human cancer chemoresistance by disrupting DNA-damage-induced apoptosis

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Июль 20, 2022

RNA-binding proteins (RBPs) play important roles in cancer development and treatment. However, the tumor-promoting RBPs their partners, which may potentially serve as therapeutic targets, need to be further identified. Here, we report that zinc finger CCHC domain-containing protein 4 (ZCCHC4) is of aberrantly high expression multiple human tissues associated with poor prognosis chemoresistance patients hepatocellular carcinoma (HCC), pancreatic colon cancer. ZCCHC4 promotes HCC cells DNA-damage agent (DDA) both vitro vivo. cell deficiency reduces tumor growth vivo intratumoral interference obviously enhances DDA-induced antitumor effect. Mechanistically, inhibits DNA-damage-induced apoptosis by interacting a new long noncoding RNA (lncRNA) AL133467.2 hamper its pro-apoptotic function. Also, blocks interaction between γH2AX upon DDA treatment inhibit apoptotic signaling promote DDAs. Knockout for enhancing chemosensitivity cells. Together, our study identifies predictor potential target improving chemotherapy effects, providing mechanistic insights partners progression chemoresistance.

Язык: Английский

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CAF-derived exosomal lncRNA FAL1 promotes chemoresistance to oxaliplatin by regulating autophagy in colorectal cancer

Digestive and Liver Disease, Год журнала: 2023, Номер 56(2), С. 330 - 342

Опубликована: Июль 1, 2023

Язык: Английский

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Mitochondrial-related drug resistance lncRNAs as prognostic biomarkers in laryngeal squamous cell carcinoma

Discover Oncology, Год журнала: 2024, Номер 15(1)

Опубликована: Дек. 18, 2024

Laryngeal squamous cell carcinoma (LSCC) is a common malignant tumor of the head and neck that significantly impacts patients' quality life, with chemotherapy resistance notably affecting prognosis. This study aims to identify prognostic biomarkers optimize treatment strategies for LSCC. Using data from The Cancer Genome Atlas (TCGA) Gene Expression Omnibus (GEO), combined mitochondrial gene database analysis, we identified lncRNAs associated drug genes. Key long non-coding RNAs (lncRNAs) were selected through univariate Cox regression Lasso regression, multivariate model was constructed predict We further analyzed differences in immune function biological pathway enrichment between high- low-risk groups, developed nomogram, compared sensitivity. Results showed based on seven could serve as an independent factor, Area Under Curve (AUC) values 0.746, 0.827, 0.771 at 1, 3, 5 years, respectively, outperforming some existing models, demonstrating high predictive performance. Significant observed sensitivity groups. risk prediction incorporating resistance-related can accurately independently prognosis LSCC patients.

Язык: Английский

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AURKB inhibition induces rhabdomyosarcoma apoptosis and ferroptosis through NPM1/SP1/ACSL5 axis

JCI Insight, Год журнала: 2025, Номер 10(3)

Опубликована: Фев. 10, 2025

Rhabdomyosarcoma (RMS) is one of the most common solid tumors in children and adolescents. Patients with relapsed/refractory RMS have limited treatment options, highlighting urgency for identification novel therapeutic targets RMS. In present study, aurora kinase B (AURKB) was found to be highly expressed associated unfavorable prognosis patients. Functional experiments indicated that inhibition AURKB significantly reduced cell proliferation, induced apoptosis ferroptosis, suppressed growth vivo. The contributes ferroptosis resistance tumor cells through nucleophosmin 1 (NPM1)/Sp1 transcription factor (SP1)/acyl-CoA synthetase long-chain family member 5 (ACSL5) axis. Furthermore, exerted an anti-RMS effect together vincristine both vitro vivo, tolerable toxicity. above findings provide insights we believe are new into tumorigenesis RMS, especially regard or resistance, indicating may a potential target clinical intervention patients

Язык: Английский

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Leveraging non-enzymatic functions of LSD1 for novel therapeutics

Trends in Pharmacological Sciences, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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