کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5525490 1546671 2017 46 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Targeting KDM1A attenuates Wnt/β-catenin signaling pathway to eliminate sorafenib-resistant stem-like cells in hepatocellular carcinoma
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی تحقیقات سرطان
پیش نمایش صفحه اول مقاله
Targeting KDM1A attenuates Wnt/β-catenin signaling pathway to eliminate sorafenib-resistant stem-like cells in hepatocellular carcinoma
چکیده انگلیسی
Use of the tyrosine kinase inhibitor sorafenib in patients with advanced hepatocellular carcinoma (HCC) is often hindered by the development of resistance, which has been recently shown to be associated with the emergence of a cancer stem cell (CSC) subpopulation. However, it remains largely unknown whether epigenetic mechanisms, especially histone posttranslational modifications, are causally linked to the maintenance of stem-like properties in sorafenib-resistant HCC. In this study, we report that the activity of lysine-specific histone demethylase 1A (KDM1A or LSD1) is required for the emergence of cancer stem cells following prolonged sorafenib treatment. As such, KDM1A inhibitors, such as pargyline and GSK2879552, dramatically suppress stem-like properties of sorafenib-resistant HCC cells. Mechanistically, KDM1A inhibitors derepress the expression of multiple upstream negative regulators of the Wnt signaling pathway to downregulate the β-catenin pathway. More importantly, KDM1A inhibition resensitizes sorafenib-resistant HCC cells to sorafenib in vivo, at least in part through reducing a CSC pool, suggesting a promising opportunity for this therapeutic combination. Together, these findings suggest that KDM1A inhibitors may be utilized to alleviate acquired resistance to sorafenib, thus increasing the therapeutic efficacy of sorafenib in HCC patients.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cancer Letters - Volume 398, 10 July 2017, Pages 12-21
نویسندگان
, , , , , , , , , , ,