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.

Linking a nuclear lncRNA to cytoplasmic lysosome integrity and cell death

“…Although all of these results are consistent with the data by KD of LCDR or hnRNPK expression to reduce LAPTM5 expression in NCI-H1299 cells, the observed LAPTM5 function in the regulation of the programmed cell death that was unrelated to other apoptosis-causing genes in Yang et al. ( 6 ) is interesting. But the data appear to contradict studies where overexpression of LAPTM5 in neuroblastoma cells was found to cause LMP and nonapoptotic cell death ( 12 ) and in HeLa cells to induce cleavage of Mcl-1, Bid, caspases, and PARP, leading to mitochondria-dependent apoptosis ( 13 ).…”

“…In PNAS, Yang et al. ( 6 ) explore the expression profile of cellular lncRNAs in the presence of the histone deacetylase inhibitor Trichostatin A and identify a ∼2-kb-long nuclear lncRNA, ENSG00000273148 or LINC00653, highly expressed from chr20 in p53-null, non–small-cell lung cancer cell line NCI-H1299 cells. Yang et al.…”

“…Yang et al. ( 6 ) show that it regulates lysosomal-associated protein transmembrane 5 (LAPTM5) expression and lysosome cell death (LCD); the authors thus name this lncRNA an LCD regulator, or LCDR.…”

“…Thus, Yang et al. ( 6 ) move one step closer to understanding how LAPTM5 promotes lysosomal membrane integrity and contributes to cancer cell survival, a finding that links LCDR and LAPTM5 as responsible for cytoplasmic lysosomal biogenesis and function.…”

“…Yang et al. ( 6 ) show that among six lysosomal proteins (ACP2, ARSB, ASAH1, GLB1, HGSNAT, and LAPTM5) susceptible to up-regulation by both LCDR and heterogenous nuclear ribonucleoprotein K (hnRNPK), short interfering RNA (siRNA)–mediated reduction of LAPTM5 expression turned out to be the only one causing lysosomal membrane permeabilization (LMP), cell apoptosis, and decreased cell proliferation and colony formation ( 6 ). Although all of these results are consistent with the data by KD of LCDR or hnRNPK expression to reduce LAPTM5 expression in NCI-H1299 cells, the observed LAPTM5 function in the regulation of the programmed cell death that was unrelated to other apoptosis-causing genes in Yang et al.…”