title: Reactive oxygen species regulate the differentiation of acute promyelocytic leukemia cells through HMGB1-mediated autophagy.
abstract: Acute promyelocytic leukemia (APL) results from a blockade of granulocyte differentiation during the promyelocytic stage. As a fusion protein of promyelocytic leukemia (PML) and retinoic acid receptor-α (RARα), PML-RARα oncoprotein is degraded through the differentiation of all-trans retinoic acid (ATRA)-induced cells. Here reactive oxygen species (ROS) and high-mobility group box 1 (HMGB1) were proven essential for the differentiation of APL cells. A down-regulation of ROS by ROS quencher (NAC) blocked the differentiation of APL cell line NB4 while an over-expression of ROS by superoxide dismutase-1 (SOD1) RNA interference (RNAi) increased cell differentiation. HMGB1 was vital for the differentiation of ROS-mediated NB4 cells and its up-regulation promoted ATRA-induced autophagy and the degradation of PML-RARα. Furthermore, ATRA treatment elevated the levels of ROS, enhanced autophagic flux and thereby promoted cytosolic translocation of HMGB1. HMGB1 regulated the interactions between ubiquitin-binding adaptor protein p62/SQSTM and PML-RARα so as to affect the degradation of PML-RARα during ATRA-induced autophagy. Also a depletion of p62/SQSTM1 expression inhibited HMGB1-mediated PML-RARα degradation and cell differentiation. The overall results suggested that HMGB1 is an essential regulator of ROS-induced cell differentiation. And it may become a potential drug target for therapeutic intervention of APL.
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University Changsha, Hunan 410008, People's Republic of China.
authors.forename: Liangchun
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Nuclear Medicine, Affiliated Tumor Hospital, Xiang-Ya Medical School, Central South University Changsha, Hunan 410008, People's Republic of China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Chai
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University Changsha, Hunan 410008, People's Republic of China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University Changsha, Hunan 410008, People's Republic of China.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University Changsha, Hunan 410008, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University Changsha, Hunan 410008, People's Republic of China.
authors.forename: Minghua
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Surgery, Hillman Cancer Center, University of Pittsburgh G.21, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University Changsha, Hunan 410008, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
keywords: HMGB1; ROS; autophagy; cell differentiation