J Cancer 2021; 12(4):1011-1022. doi:10.7150/jca.48310 This issue

Research Paper

EHMT2 inhibitor BIX-01294 induces endoplasmic reticulum stress mediated apoptosis and autophagy in diffuse large B-cell lymphoma cells

Linyan Xu1,2,3*, Xiang Gao1,3*, Pu Yang4*, Wei Sang1,2,3, Jun Jiao1,3, Mingshan Niu1,2,3, Mengdi Liu1,3, Yuanyuan Qin1,3, Dongmei Yan2, Xuguang Song2, Cai Sun2, Yu Tian2, Feng Zhu1,2,3, Xiaoshen Sun1,3, Lingyu Zeng1,2,3, Zhenyu Li1,2,3, Kailin Xu1,2,3✉

1. Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.
2. Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
3. Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu, China.
4. Department of Hematology, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan, China.
*Equal contributors to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Xu L, Gao X, Yang P, Sang W, Jiao J, Niu M, Liu M, Qin Y, Yan D, Song X, Sun C, Tian Y, Zhu F, Sun X, Zeng L, Li Z, Xu K. EHMT2 inhibitor BIX-01294 induces endoplasmic reticulum stress mediated apoptosis and autophagy in diffuse large B-cell lymphoma cells. J Cancer 2021; 12(4):1011-1022. doi:10.7150/jca.48310. Available from https://www.jcancer.org/v12p1011.htm

File import instruction

Abstract

Graphic abstract

Despite advancement in the treatment of diffuse large B-cell lymphoma (DLBCL), many patients tend to relapse or become refractory after initial therapy. Therefore, it is essential to identify novel therapeutic targets and drugs, understand the molecular pathogenesis mechanism of DLBCL, and find ways to prevent and treat relapsed or refractory DLBCL. BIX-01294 is a small molecule compound that specifically inhibits EHMT2 activity. In this study, we demonstrate that BIX-01294 triggered the inhibition of human DLBCL cell proliferation, lead to G1 phase arrest via increasing P21 level and reducing cyclin E level. BIX-01294 also induced apoptosis via endogenous and exogenous apoptotic pathways. Moreover, BIX-01294 triggered autophagy and activated ER stress in human DLBCL cells. Furthermore, we showed that both key components of ER stress, ATF3, and ATF4, are required for BIX-01294-induced apoptosis and autophagy. Hence, this study provides new evidence that EHMT2 may be a new therapeutic target, and BIX-01294 may be a potential therapeutic drug for treating DLBCL.

Keywords: apoptosis, autophagy, BIX-01294, diffuse large B cell lymphoma, endoplasmic reticulum stress