Ibuprofen promotes p75 neurotrophin receptor expression through modifying promoter methylation and N6-methyladenosine-RNA-methylation in human gastric cancer cells

Abstract

It is acknowledged that nonsteroidal anti-inflammatory drugs (NSAIDs) can participate in various signaling pathways, while information about their epigenetic effects are limited. p75NTR (p75 neurotrophin receptor) can inhibit tumor growth by inducing cell cycle arrest and regulating cell cycle arrest and apoptotic cell death. The expression of p75NTR is influenced by epigenetic roles. We explored the effects of ibuprofen on p75NTR expression and investigated whether promoter methylation and N6-methyladenosine (m6A) RNA methylation regulates this process in human gastric cancer cells (SGC7901 and MKN45). Cell lines were treated with ibuprofen 0, 2.5, 5, 10, 20 µM, and then DNA, RNA, and protein were isolated 24 h later. Expression and promoter methylation of p75NTR were detected by RT-qPCR and Western blot. The levels of m6A-p75NTR were measured by RNA immunoprecipitation. We also used RT-qPCR to determine the levels of m6A-related regulators, METTL3, METTL14, ALKBH5, FTO, YTHDC2, and YTHDF1-3. Ibuprofen attenuated p75NTR promoter methylation ( p < 0.01) and increased p75NTR level ( p < 0.001). Ibuprofen increased m6A-p53 expression ( p < 0.01) by promoting the expression of METTL3 ( p < 0.01) and METTL14 ( p < 0.05); and increased levels of YTHDF1 ( p < 0.001), YTHDF3 ( p < 0.001), and YTHDC2 ( p < 0.01) that finally reinforced p53 translation ( p < 0.01). Therefore, our results present that ibuprofen epigenetically increased p75NTR expression by downregulating promoter methylation and upregulating m6A-RNA-methylation in SGC7901 and MKN45 cells. Our study unveils a novel mechanism for p75NTR regulation by NSAIDs and helps the design of treatment targets.

METTL14‑mediated RNA methylation in digestive system tumors

“…LHPP overexpression can also inhibit the Wnt signaling pathway, which consequently inhibits the phosphorylation of GSK-3β and aerobic glycolysis in GC cells ( 71 ). Jin et al ( 72 ) reported that ibuprofen treatment can promote the expression of METTL3 and METTL14 in GC cells. METTL3 and METTL14 can also promote p53 translation, which in turn epigenetically increases p75 neurotrophin receptor (p75NTR) expression ( 72 ).…”

“…Jin et al ( 72 ) reported that ibuprofen treatment can promote the expression of METTL3 and METTL14 in GC cells. METTL3 and METTL14 can also promote p53 translation, which in turn epigenetically increases p75 neurotrophin receptor (p75NTR) expression ( 72 ). p75NTR is considered to be a potential tumor suppressor that is associated with proliferation inhibition ( 72 ).…”

The Nerve Growth Factor Receptor (NGFR/p75NTR): A Major Player in Alzheimer’s Disease

“…Moreover, preliminary data indicated that NGFR/p75 NTR can also undergo epigenetic modifications such as methylation and histone acetylation. For example, it has been shown that ibuprofen can increase the mRNA and protein levels of NGFR/p75 NTR by inducing its promoter hypomethylation and by increasing N 6 -methyladenosine (m6A)-NGFR/p75 NTR expression in cancer cell lines [ 41 ].…”

The Nerve Growth Factor Receptor (NGFR/P75^ntr): A Major Player in Alzheimer’s Disease

“…Moreover, preliminary data indicated that NGFR/p75 NTR can also undergo epigenetic modifications such as methylation and histone acetylation. For example, it has been shown that ibuprofen can increase the mRNA and protein levels of NGFR/p75 NTR by inducing its promoter hypomethylation and by increasing N 6 -methyladenosine (m6A)-NGFR/p75 NTR expression in cancer cell lines [36].…”