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

ABSTRACT: Long noncoding RNAs (lncRNAs) play pivotal roles in tumor development, but little is known about their involvement in the early steps of tumorigenesis. To identify lncRNAs dysregulated in precancerous lesions, we analyzed genome-wide trimethylation of histone H3 lysine 4 (H3K4me3) to screen for transcriptionally active lncRNA genes in the nontumorous gastric mucosa of patients with gastric cancer (GC) and healthy individuals. We found that H3K4me3 at TM4SF1-AS1 is specifically upregulated in GC patients and that expression of TM4SF1-AS1 is prevalently 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 interaction with Pur-α and YB-1. Chromatin isolation by RNA purification (ChIRP)-mass spectrometry demonstrated that TM4SF1‑AS1 associates with several stress granule (SG)-related proteins, including G3BP2, RACK1 and DDX3. Notably, TM4SF1-AS1 promotes SG formation and inhibits apoptosis in GC cells by sequestering RACK1, an activator of the stress-responsive MAPK pathway, within SGs. TM4SF1‑AS1-induced SG formation and apoptosis inhibition are dependent on Pur-α and YB-1. These findings suggest TM4SF1-AS1 contributes to tumorigenesis by enhancing SG-mediated stress adaptation.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Hiromu Suzuki

PROVIDER: PXD036766 | JPOST Repository | Sat Sep 16 00:00:00 BST 2023

REPOSITORIES: jPOST

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Project description:Recent studies suggest that telomerase promotes cell growth by mechanisms that extend beyond the rescue of critically short telomeres. The in vitro model of mTert overexpressing MEFs recapitulates fundamental aspects of the growth-promoting effects of mTert in vivo. First, in Terc-proficient cells, mTert overexpression favors escape from replicative senescence and enhances anchorage-independent growth in response to oncogenic stress, which fits well with previous data showing that mTert overexpression promotes tumor formation. Second, in Terc-deficient cells, retroviral transduction with mTert results in a delayed onset of immortalization and impairs colony formation in response to oncogenic stress, which is in agreement with the inhibitory effect of mTert overexpression on tumorigenesis in a Terc null mouse background. To unravel the molecular targets of telomerase that impact on cell growth, we compared the transcriptome of MEFs, before and after mTert introduction. We found that ectopic expression of mTert was associated with detectable gene expression changes (greater than 1.5-fold; validated by qRT-PCR) of 26 transcripts. Analysis of the observed transcriptional changes indicates that ectopic expression of mTert suppresses in a coordinated manner functionally related genes with overlapping roles in growth arrest, resistance to transformation, and apoptosis. We show that the majority of the telomerase target genes are growth-inhibitory, transforming growth factor-beta (TGF-beta) -inducible genes and provide functional evidence for the potential of telomerase to abrogate TGF-beta -mediated growth inhibition. Thus, in line with the current view that the diversity of TGF-beta responses is not so much a consequence of the use of different signaling pathways but caused by different ways of reading the output from the same basic pathway, we propose that the telomerase status of a cell creates a gene expression pattern that determines how cells read growth inhibitory signals, among them signals propagated through the TGF-beta pathway.

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

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