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

Mar 28, 2022FASEB journal : official publication of the Federation of American Societies for Experimental Biology

RNA demethylase ALKBH5 may block TGF-β-induced cell changes linked to lung cancer by controlling TGF-β/SMAD signaling

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Abstract

ALKBH5 expression is significantly reduced in metastatic non-small-cell lung cancer (NSCLC).

Overexpression of ALKBH5 inhibits TGF-β-induced epithelial-mesenchymal transition (EMT) and invasion in NSCLC cells.
Knockdown of ALKBH5 promotes TGF-β-induced EMT and invasion.
ALKBH5 overexpression suppresses TGF-β-stimulated metastasis in vivo.
ALKBH5 influences the expression and stability of TGFβR2 and SMAD3 mRNA, while affecting SMAD6 levels in the opposite manner.
ALKBH5 alters the phosphorylation of SMAD3, a key component of TGF-β signaling.
mA-binding proteins YTHDF1/2/3 modulate the expression of TGFβR2, SMAD3, and SMAD6 in NSCLC cells.

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AlkB homolog 5 (ALKBH5) has been revealed as a key RNA N-methyladenosine (mA) 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, mA-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 mA 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. 6 6 6 6

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

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