title: Targeting KDM1A attenuates Wnt/β-catenin signaling pathway to eliminate sorafenib-resistant stem-like cells in hepatocellular carcinoma.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, People's Republic of China.
authors.forename: Mengxi
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, People's Republic of China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Geng
authors.affiliation: Department of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing, Jiangsu Province, People's Republic of China.
authors.forename: Dong
authors.initials: D
authors.lastname: Han
authors.affiliation: Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing, Jiangsu Province, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Xie
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, People's Republic of China.
authors.forename: Liya
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing, Jiangsu Province, People's Republic of China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Gastroenterology Department, Bethune International Peace Hospital (of the People's Liberation Army), Shijiazhuang City, Hebei Province, People's Republic of China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, People's Republic of China. Electronic address: leizengjie@163.com.
authors.forename: Zengjie
authors.initials: Z
authors.lastname: Lei
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, People's Republic of China. Electronic address: chuxiaoyuan000@163.com.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D003521:Cyclopropanes / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010293:Pargyline / Q000494:pharmacology*; D010641:Phenotype; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034622:RNA Interference; D000077157:Sorafenib; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; D003521:Cyclopropanes; C000602008:GSK2879552; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D010293:Pargyline; D000077157:Sorafenib; D056466:Histone Demethylases; C495195:KDM1A protein, human
keywords: Cancer stem cell; Hepatocellular carcinoma; Histone demethylation; KDM1A inhibitor; Sorafenib resistance