YTHDF2 exerts tumor-suppressor roles in gastric cancer via up-regulating PPP2CA independently of m6A modification

Abstract

Background YTHDF2 is one of important readers of N6-methyladenosine (m6A) modification on RNA. Growing evidence implicates that YTHDF2 takes an indispensable part in the regulation of tumorigenesis and metastasis in different cancers, but its biological functions and underlying mechanisms remain elusive in gastric cancer (GC). Aim To investigate the clinical relevance and biological function of YTHDF2 in GC. Results Compared with matched normal stomach tissues, YTHDF2 expression was markedly decreased in gastric cancer tissues. The expression level of YTHDF2 was inversely associated with gastric cancer patients’ tumor size, AJCC classification and prognosis. Functionally, YTHDF2 reduction facilitated gastric cancer cell growth and migration in vitro and in vivo, whereas YTHDF2 overexpression exhibited opposite phenotypes. Mechanistically, YTHDF2 enhanced expression of PPP2CA, the catalytic subunit of PP2A (Protein phosphatase 2A), in an m6A-independent manner, and silencing of PPP2CA antagonized the anti-tumor effects caused by overexpression of YTHDF2 in GC cells. Conclusion These findings demonstrate that YTHDF2 is down-regulated in GC and its down-regulation promotes GC progression via a possible mechanism involving PPP2CA expression, suggesting that YTHDF2 may be a hopeful biomarker for diagnosis and an unrevealed treatment target for GC.

N6‐methyladenosine methyltransferase METTL3 modulates the cell cycle of granulosa cells via CCND1 and AURKB in Haimen goats

“…During recent decades, a massive number of studies have revealed that YTHDF2 destabilizes m6A-containing RNA, [9][10][11] and studies also have reported that there are m6A sites in AURKB mRNA. 39,40 Our results showed that the knockdown of METTL3 led to a downregulation of m6A modification in AURKB, which may subsequently inhibit the decay of AURKB mRNA in an m6A-YT-HDF2-dependent manner within goat granulosa cells.…”

“…The core components of writers include methyltransferase‐like 3 (METTL3), METTL14, and Wilms tumor 1 associated protein (WTAP), while examples of erasers in mammals include alkB homolog 5 (ALKBH5) and fat mass and obesity‐associated protein (FTO). YTH N6‐Methyladenosine RNA Binding Protein 2 (YTHDF2) is one of the m6A “readers” that decodes the m6A mark and mediates RNA decay along with other proteins 9–11 . While many studies have reported on the functions of m6A in ovary development, 6,12–14 the mechanism by which m6A participates in oocyte maturation through granulosa cells in mammals, especially domestic animals, has not been fully elucidated.…”

“…YTH N6-Methyladenosine RNA Binding Protein 2 (YTHDF2) is one of the m6A "readers" that decodes the m6A mark and mediates RNA decay along with other proteins. [9][10][11] While many studies have reported on the functions of m6A in ovary development, 6,[12][13][14] the mechanism by which m6A participates in oocyte maturation through granulosa cells in mammals, especially domestic animals, has not been fully elucidated.…”

The crosstalk between the RNA demethylase, non‐coding RNAs, and transcription factors in gastric cancer: An ALKBH5 perspective

“…YTHDF2 is a noteworthy reader protein that has been proven to be overexpressed in GC tissues and cell lines and involved in gastric carcinogenesis by regulating mRNA metabolism and translation. Functionally speaking, YTHDF2 knockdown could dramatically inhibit the proliferation, migration, and invasion of GC cells 27 . But the mechanism of the tumor‐promoting mechanism of YTHDF2 remains inconclusive.…”

“…Functionally speaking, YTHDF2 knockdown could dramatically inhibit the proliferation, migration, and invasion of GC cells. 27 But the mechanism of the tumorpromoting mechanism of YTHDF2 remains inconclusive. In Fang's work, LINC00659 was found responsible for the formation of the ALKBH5 complex, which is required for the binding with JAK1 mRNA.…”