Lysine demethylase LSD1 delivered via small extracellular vesicles promotes gastric cancer cell stemness

TY - JOUR

T1 - Lysine demethylase LSD1 delivered via small extracellular vesicles promotes gastric cancer cell stemness

AU - Zhao, Li Juan

AU - Li, Ying Ying

AU - Zhang, Yu Tong

AU - Fan, Qi Qi

AU - Ren, Hong Mei

AU - Zhang, Cheng

AU - Mardinoglu, Adil

AU - Chen, Wen Chao

AU - Pang, Jing Ru

AU - Shen, Dan Dan

AU - Wang, Jun Wei

AU - Zhao, Long Fei

AU - Zhang, Jian Ying

AU - Wang, Zhen Ya

AU - Zheng, Yi Chao

AU - Liu, Hong Min

N1 - Funding Information: This work was supported by the National Natural Science Foundation of China (No. 81602961, No. 81430085, and No. 21372206), the National Key Research Program (No. 2018YFE0195100, No. 2016YFA0501800, and No. 2017YFD0501401); Science and Technology Innovation Talents of Henan Provincial Education Department (19IRTSTHN001), Basic and Frontier Technology Research Project of Henan Province (No. 162300410119), and the Natural Science Foundation of Henan Province (No. 162300410292). Publisher Copyright: © 2021 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/8/4

Y1 - 2021/8/4

N2 - Several studies have examined the functions of nucleic acids in small extracellular vesicles (sEVs). However, much less is known about the protein cargos of sEVs and their functions in recipient cells. This study demonstrates the presence of lysine-specific demethylase 1 (LSD1), which is the first identified histone demethylase, in the culture medium of gastric cancer cells. We show that sEVs derived from gastric cancer cells and the plasma of patients with gastric cancer harbor LSD1. The shuttling of LSD1-containing sEVs from donor cells to recipient gastric cancer cells promotes cancer cell stemness by positively regulating the expression of Nanog, OCT4, SOX2, and CD44. Additionally, sEV-delivered LSD1 suppresses oxaliplatin response of recipient cells in vitro and in vivo, whereas LSD1-depleted sEVs do not. Taken together, we demonstrate that LSD1-loaded sEVs can promote stemness and chemoresistance to oxaliplatin. These findings suggest that the LSD1 content of sEV could serve as a biomarker to predict oxaliplatin response in gastric cancer patients.

AB - Several studies have examined the functions of nucleic acids in small extracellular vesicles (sEVs). However, much less is known about the protein cargos of sEVs and their functions in recipient cells. This study demonstrates the presence of lysine-specific demethylase 1 (LSD1), which is the first identified histone demethylase, in the culture medium of gastric cancer cells. We show that sEVs derived from gastric cancer cells and the plasma of patients with gastric cancer harbor LSD1. The shuttling of LSD1-containing sEVs from donor cells to recipient gastric cancer cells promotes cancer cell stemness by positively regulating the expression of Nanog, OCT4, SOX2, and CD44. Additionally, sEV-delivered LSD1 suppresses oxaliplatin response of recipient cells in vitro and in vivo, whereas LSD1-depleted sEVs do not. Taken together, we demonstrate that LSD1-loaded sEVs can promote stemness and chemoresistance to oxaliplatin. These findings suggest that the LSD1 content of sEV could serve as a biomarker to predict oxaliplatin response in gastric cancer patients.

KW - gastric cancer

KW - LSD1

KW - small extracellular vesicles

KW - stemness

UR - http://www.scopus.com/inward/record.url?scp=85107325592&partnerID=8YFLogxK

U2 - 10.15252/embr.202050922

DO - 10.15252/embr.202050922

M3 - Article

C2 - 34060205

AN - SCOPUS:85107325592

SN - 1469-221X

VL - 22

JO - EMBO Reports

JF - EMBO Reports

IS - 8

M1 - e50922

ER -