TM4SF1-AS1 inhibits apoptosis by promoting stress granule formation in cancer cells

Abstract

Long noncoding RNAs (lncRNAs) play pivotal roles in tumor development; however, little is known about their involvement in the early stages of tumorigenesis. To identify dysregulated lncRNAs in precancerous lesions, we analyzed genome-wide trimethylation of histone H3 lysine 4 (H3K4me3) to screen for transcriptionally active lncRNA genes in the non-tumorous gastric mucosa of patients with gastric cancer (GC) and healthy individuals. We found that H3K4me3 at TM4SF1-AS1 was specifically upregulated in GC patients and that the expression of TM4SF1-AS1 was significantly elevated in primary and cultured GC cells. TM4SF1-AS1 contributes to GC cell proliferation in vitro and in vivo, and its oncogenic function is mediated, at least in part, through interactions with purine-rich element-binding protein α (Pur-α) and Y-box binding protein 1 (YB-1). TM4SF1-AS1 also activates interferon signaling in GC cells, which is dependent on Pur-α and RIG-I. Chromatin isolation by RNA purification (ChIRP)-mass spectrometry demonstrated that TM4SF1AS1 was associated with several stress granule (SG)-related proteins, including G3BP2, RACK1, and DDX3. Notably, TM4SF1-AS1 promoted SG formation and inhibited apoptosis in GC cells by sequestering RACK1, an activator of the stress-responsive MAPK pathway, within SGs. TM4SF1AS1-induced SG formation and apoptosis inhibition are dependent on Pur-α and YB-1. These findings suggested that TM4SF1-AS1 contributes to tumorigenesis by enhancing SG-mediated stress adaptation.

Activation of the mitochondrial unfolded protein response regulates the formation of stress granules

“…Questions remain as to the functional link between inhibition of SG assembly and mitochondrial homeostasis following UPRmt activation. Several studies support a protective role for SGs, through impairing pro-apoptotic JNK signalling (Arimoto et al, 2008; Kitajima et al, 2023), sequestration of caspases (Fujikawa et al, 2023) or suppressing production of ROS (Park and Shin, 2023; Takahashi et al, 2013) and they have been described as “shock absorbers” dampening excessive innate immune response to viral infection (Paget et al, 2023). In contrast, persistent SGs are implicated in pro-death functions during chronic stress conditions as well as neurodegenerative diseases or tumour chemotherapy (Reineke et al, 2018; Reineke and Neilson, 2019; Schwed-Gross et al, 2022).…”