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

Author:

Kitajima Hiroshi1ORCID,Maruyama Reo2,Niinuma Takeshi1,Yamamoto Eiichiro1,Takasawa Akira1,Takasawa Kumi1,Ishiguro Kazuya1,Tsuyada Akihiro1,Suzuki Ryo1,Sudo Gota1,Kubo Toshiyuki1,Mitsuhashi Kei1,Idogawa Masashi1ORCID,Tange Shoichiro1,Toyota Mutsumi1,Yoshido Ayano1,Kumegawa Kohei3,Kai Masahiro1,Yanagihara Kazuyoshi4,Tokino Takashi1,Osanai Makoto1,Nakase Hiroshi1ORCID,Suzuki Hiromu5ORCID

Affiliation:

1. Sapporo Medical University School of Medicine

2. The Cancer Institute, Japanese Foundation for Cancer

3. Japanese Foundation for Cancer Research

4. National Cancer Center Research Institute

5. Sapporo Medical University

Abstract

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.

Publisher

Research Square Platform LLC

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