RNA demethylase ALKBH5 inhibits TGF‐β‐induced EMT by regulating TGF‐β/SMAD signaling in non‐small cell lung cancer

Abstract

AlkB homolog 5 (ALKBH5) has been revealed as a key RNA N6‐methyladenosine (m6A) demethylase that is implicated in development and diseases. However, the function of ALKBH5 in TGF‐β‐induced epithelial‐mesenchymal transition (EMT) and tumor metastasis of non‐small‐cell lung cancer (NSCLC) remains unknown. Here, we firstly show that ALKBH5 expression is significantly reduced in metastatic NSCLC. ALKBH5 overexpression inhibits TGF‐β‐induced EMT and invasion of NSCLC cells, whereas ALKBH5 knockdown promotes the corresponding phenotypes. ALKBH5 overexpression suppresses TGF‐β‐stimulated NSCLC cell metastasis in vivo. ALKBH5 overexpression decreases the expression and mRNA stability of TGFβR2 and SMAD3 but increases those of SMAD6, while ALKBH5 knockdown causes the opposite results. Importantly, ALKBH5 overexpression or knockdown leads respectively to an attenuated or augmented phosphorylation of SMAD3, an indispensable downstream effector that activates TGF‐β/SMAD signaling. Moreover, m6A‐binding proteins YTHDF1/3 promotes TGFβR2 and SMAD3 expression, and YTHDF2 inhibits SMAD6 expression. YTHDF1/2/3 facilitates TGF‐β‐stimulated EMT and invasion of NSCLC cells. Mechanistically, ALKBH5 affects TGFβR2, SMAD3 and SMAD6 expression and mRNA stability by erasing m6A modification in NSCLC cells. ALKBH5 weakens YTHDF1/3‐mediated TGFβR2 and SMAD3 mRNA stabilization, and abolishes YTHDF2‐mediated SMAD6 mRNA degradation, supporting the notion that ALKBH5 inhibits TGF‐β‐induced EMT and invasion of NSCLC cells via YTHD1/2/3‐mediated mechanism. Taken together, our findings highlight an important role of ALKBH5 in regulating TGF‐β/SMAD signaling, and establish a mechanistic interaction of ALKBH5 with TGFβR2/SMAD3/SMAD6 for controlling TGF‐β‐induced EMT in NSCLCs.

The function and clinical implication of YTHDF1 in the human system development and cancer

“…Gao et al demonstrated that LINC00337 is positively regulated by sponging YTHDF1, with the subsequent promotion of LUAD progression [ 60 ]. Zhang et al found that YTHDF1-mediated TGFβR2 mRNA stabilization and increased expression promote the EMT of NSCLC [ 84 ]. It has been shown that YTHDF1 is up-regulated in 5-fluorouracil (5-FU) and oxaliplatin-resistant NSCLC cells whereas knockdown of YTHDF1 boosts the cisplatin resistance of NSCLC via modulates the Keap1-Nrf2-AKR1C1 axis [ 22 ].…”

Stage-specific requirement for METTL3-dependent m6A modification during dental pulp stem cell differentiation

“…METTL3-mediated m 6 A modification regulates the expression of some osteogenic markers and other related genes involved in bone metabolism [32]. Parathyroid hormone (PTH)/ Pth1r, TGF-β/SMAD, WNT and other signaling pathways are modulated by m 6 A marks, which are essential in the cellular differentiation and cancer development [16,33,34]. Here, NOG and downstream Smad pathway were identified as the target of METTL3-mediated m 6 A modification during DPSC differentiation.…”

Cancer-associated fibroblasts promote migration and invasion of non-small cell lung cancer cells via METTL3-mediated RAC3 m6A modification

“…lncRNA AC098934 enhanced the invasion of lung adenocarcinoma cells through METTL3-mediated m 6 A modification in AC098934 [31]. ALKBH5 inhibited TGF-β/SMAD signaling and suppressed TGF-β-induced epithelial-mesenchymal transition (EMT) through reducing m 6 A modifications in NSCLC cells [32]. However, whether m 6 A modification is responsible for the CAFs' effect on lung cancer metastasis has not been evaluated.…”