HOTAIR Knockdown Increases the Sensitivity of Hepatocellular Carcinoma Cells to Sorafenib by Disrupting miR-145-5p/HK2 Axis-Mediated Mitochondrial Function and Glycolysis
Background: Frequent drug resistance seriously limits the therapeutic efficacy of sorafenib in advanced hepatocellular carcinoma (HCC). Strategies to increase the response to sorafenib are limited, and the underlying mechanism to facilitate such an increase is not entirely underst...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
IMR Press
2025-05-01
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| Series: | Frontiers in Bioscience-Landmark |
| Subjects: | |
| Online Access: | https://www.imrpress.com/journal/FBL/30/5/10.31083/FBL37368 |
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| Summary: | Background: Frequent drug resistance seriously limits the therapeutic efficacy of sorafenib in advanced hepatocellular carcinoma (HCC). Strategies to increase the response to sorafenib are limited, and the underlying mechanism to facilitate such an increase is not entirely understood. Homeobox (HOX) transcript antisense intergenic RNA (HOTAIR) expression is high in HCC, promoting the occurrence and progression of HCC. In this study, we explored the mechanism through which HOTAIR knockdown affects the response of HCC cells to the chemotherapeutic sorafenib. Methods: Cell viability and apoptosis were assessed using MTT assay, flow cytometry, and nuclear staining. Mitochondrial function and isolation were determined using flow cytometry and a mitochondrial isolation kit. Glycolysis was measured by glucose and lactic acid assay kits. The underlying mechanisms were explored through western blotting, quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and chromatin immunoprecipitation (ChIP). Results: HOTAIR knockdown increased sorafenib-induced apoptosis in the HCC cells. HOTAIR and hexokinase 2 (HK2) expression levels were upregulated in human HCC tissues, demonstrating a significant correlation. The knockdown of HOTAIR or HK2 aggravated mitochondrial dysfunction and inhibited glycolysis. Further, HOTAIR knockdown promoted sorafenib-mediated HK2 mRNA downregulation, resulting in decreased HK2 protein levels in cells and mitochondria. This ultimately facilitated the mitochondrial apoptotic pathway. Moreover, it was demonstrated that HOTAIR regulated HK2 via polycomb repressive complex 2 (PRC2)-mediated epigenetic modification of miR-145-5p in HCC. Conclusions: HOTAIR knockdown increased the sensitivity of HCC cells to sorafenib by disrupting the miR-145-5p/HK2 axis-mediated mitochondrial function and glycolysis, suggesting new strategies for HCC treatment. |
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| ISSN: | 2768-6701 |