Inhibition of EZH2 Attenuates Sorafenib Resistance by Targeting NOTCH1 Activation-Dependent Liver Cancer Stem Cells via NOTCH1-Related MicroRNAs in Hepatocellular Carcinoma
| Autor: | Shanshan Wang, Fengwei Zhang, Rong Xiao, Xuechai Shang, Long Cai, Hongjuan Zhou |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Sorafenib Cancer Research Original article macromolecular substances lcsh:RC254-282 03 medical and health sciences 0302 clinical medicine Cancer stem cell microRNA medicine neoplasms biology business.industry EZH2 medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens digestive system diseases 030104 developmental biology Histone Oncology 030220 oncology & carcinogenesis Hepatocellular carcinoma biology.protein Cancer research Stem cell Liver cancer business medicine.drug |
| Zdroj: | Translational Oncology Translational Oncology, Vol 13, Iss 3, Pp-(2020) |
| ISSN: | 1936-5233 |
| Popis: | Acquired resistance and intrinsic to sorafenib therapy represents a major hurdle in improving the management of advanced hepatocellular carcinoma (HCC), which has been recently shown to be associated with the emergence of liver cancer stem cells (CSCs). However, it remains largely unknown whether and how histone posttranslational modifications, especially H3K27me3, are causally linked to the maintenance of self-renewal ability in sorafenib-resistant HCC. Here, we found that NOTCH1 signaling was activated in sorafenib-resistant HCC cells and NOTCH1 activation conferred hepatoma cells sorafenib resistance through enhanced self-renewal and tumorigenecity. Besides, the overexpression of EZH2 was required for the emergence of cancer stem cells following prolonged sorafenib treatment. As such, modulating EZH2 expression or activity suppressed activation of NOTCH1 pathway by elevating the expression of NOTCH1-related microRNAs, hsa-miR-21-5p and has-miR-26a-1-5p, via H3K27me3, and consequently weakened self-renewal ability and tumorigenecity and restored the anti-tumor effects of sorafenib. Overall, our results highlight the role of EZH2/NICD1 axis, and also suggest that EZH2 and NOTCH1 pathway are rational targets for therapeutic intervention in sorafenib-resistant HCC. |
| Databáze: | OpenAIRE |
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