LCDR regulates the integrity of lysosomal membrane by hnRNP K-stabilized LAPTM5 transcript and promotes cell survival.

Abstract

Lysosome plays important roles in cellular homeostasis, and its dysregulation contributes to tumor growth and survival. However, the understanding of regulation and the underlying mechanism of lysosome in cancer survival is incomplete. Here, we reveal a role for a histone acetylation-regulated long noncoding RNA termed lysosome cell death regulator (LCDR) in lung cancer cell survival, in which its knockdown promotes apoptosis. Mechanistically, LCDR binds to heterogenous nuclear ribonucleoprotein K (hnRNP K) to regulate the stability of the lysosomal-associated protein transmembrane 5 (LAPTM5) transcript that maintains the integrity of the lysosomal membrane. Knockdown of LCDR, hnRNP K, or LAPTM5 promotes lysosomal membrane permeabilization and lysosomal cell death, thus consequently resulting in apoptosis. LAPTM5 overexpression or cathepsin B inhibitor partially restores the effects of this axis on lysosomal cell death in vitro and in vivo. Similarly, targeting LCDR significantly decreased tumor growth of patient-derived xenografts of lung adenocarcinoma (LUAD) and had significant cell death using nanoparticles (NPs)-mediated systematic short interfering RNA delivery. Moreover, LCDR/hnRNP K/LAPTM5 are up-regulated in LUAD tissues, and coexpression of this axis shows the increased diagnostic value for LUAD. Collectively, we identified a long noncoding RNA that regulates lysosome function at the posttranscriptional level. These findings shed light on LCDR/hnRNP K/LAPTM5 as potential therapeutic targets, and targeting lysosome is a promising strategy in cancer treatment.

• Authors: Xiwang Yang, Ya Wen, Shaomin Liu, Liqiang Duan, Tongfeng Liu, Zhou Tong, Zhuo Wang, Yinmin Gu, Yibo Xi, Xiaodong Wang, Dingsan Luo, Ruobing Zhang, Yajuan Liu, Yang Wang, Tianyou Cheng, Siyuan Jiang, Xiaofeng Zhu, Xiaohui Yang, Yongbo Pan, Shuwen Cheng, Qinong Ye, Jinfei Chen, Xiaoding Xu, Shan Gao
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 119 Issue 5 (02 01 2022) ISSN: 1091-6490 [Electronic] United States
• PMID: 35091468 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 the Author(s). Published by PNAS.

Chemical References

• Heterogeneous-Nuclear Ribonucleoprotein K
• Membrane Proteins
• RNA, Long Noncoding
• HNRNPK protein, human
• LAPTM5 protein, human

Topics

• Apoptosis (genetics)
• Cell Death
• Cell Line, Tumor
• Cell Survival
• China
• Gene Expression (genetics)
• Gene Expression Regulation, Neoplastic (genetics)
• Heterogeneous-Nuclear Ribonucleoprotein K (genetics, metabolism)
• Humans
• Intracellular Membranes (metabolism)
• Lysosomes (metabolism)
• Membrane Proteins (metabolism)
• Neoplasms (genetics)
• RNA, Long Noncoding (genetics)