title: KDM4C, a H3K9me3 Histone Demethylase, is Involved in the Maintenance of Human ESCC-Initiating Cells by Epigenetically Enhancing SOX2 Expression.
abstract: Our studies investigating the existence of tumor-initiating cell (TIC) populations in human esophageal squamous cell carcinoma (ESCC) had identified a subpopulation of cells isolated from ESCC patient-derived tumor specimens marked by an ALDHbri+phenotype bear stem cell-like features. Importantly, KDM4C, a histone demethylase was enhanced in ALDHbri+subpopulation, suggesting that strategies interfering with KDM4C may be able to target these putative TICs. In the present study, by genetic and chemical means, we demonstrated that, KDM4C blockade selectively decreased the ESCC ALDHbri+TICs population in vitro and specifically targeted the TICs in ALDHbri+-derived xenograft, retarding engraftment. Subsequent studies of the KDM4C functional network identified a subset of pluripotency-associated genes (PAGs) and aldehyde dehydrogenase family members to be preferentially down-regulated in KDM4C inhibited ALDHbri+TICs. We further supported a model in which KDM4C maintains permissive histone modifications with a low level of H3K9 methylation at the promoters of several PAGs. Moreover, ectopic expression of SOX2 restored KDM4C inhibition-dependent ALDHbri+TIC properties. We further confirmed these findings by showing that the cytoplasmic and nuclear KDM4C staining increased with adverse pathologic phenotypes and poor patient survival. Such staining pattern of intracellular KDM4C appeared to overlap with the expression of SOX2 and ALDH1. Collectively, our findings provided the insights into the development of novel therapeutic strategies based on the inhibition of KDM4C pathway for the eliminating of ESCC TIC compartment.
authors.affiliation: Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China. Electronic address: yuanxiangdrive@163.com.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China. Electronic address: kongjinyu@126.com.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Kong
authors.affiliation: Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China. Electronic address: mazhikun1225@163.com.
authors.forename: Zhikun
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China. Electronic address: linatec83@163.com.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China. Electronic address: ruinuojia78@163.com.
authors.forename: Ruinuo
authors.initials: R
authors.lastname: Jia
authors.affiliation: Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China. Electronic address: liuyiwen615810@163.com.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Thoracic Surgery, Anyang Tumor Hospital, Anyang, Henan, China.
authors.forename: Fuyou
authors.initials: F
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking, China. Electronic address: qmzhan59@163.com.
authors.forename: Qimin
authors.initials: Q
authors.lastname: Zhan
authors.affiliation: Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China; Barbara Ann Karmanos Cancer Institute and Department of Oncology, Wayne State University, 4100 John R, Detroit, MI 48201. Electronic address: liuga@karmanos.org.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China. Electronic address: gsgvicepresident@163.com.
authors.forename: Shegan
authors.initials: S
authors.lastname: Gao