Fto-mediated m⁶A demsupplementethylation of SNHG9 Enhances PINK1-Dependent mitophagy and reverses cisplatin resistance via nuclear EZH2 ubiquitination.

Authors

Zihan Jing, Xingmei Ren, Ruqiong Wang, Bo An, Weitong Gao, Yan Jin, Lihua Shang, Dexin Jia, Yan Yu

Published in

Biochemical pharmacology. Pages 118345. Aug 14, 2026. Epub Aug 14, 2026.

Abstract

Cisplatin (CDDP) resistance in lung adenocarcinoma (LUAD) is associated with increased N⁶-methyladenosine (m⁶A) RNA modification. Although proteolysis-targeting chimeras (PROTACs) that recruit E3 ligases have shown therapeutic potential, the role of nuclear ubiquitination in CDDP resistance remains unclear. Here, m⁶A-epitranscriptomic profiling identified the long non-coding RNA small nucleolar RNA host gene 9 (SNHG9) as a key target of the m⁶A demethylase fat mass and obesity-associated protein (FTO). Clinically, elevated SNHG9 expression was associated with poor prognosis and CDDP resistance. Mechanistically, SNHG9 bound to and inhibited the E3 ligase von Hippel-Lindau tumor suppressor protein (VHL), thereby blocking VHL-mediated ubiquitination and proteasomal degradation of enhancer of zeste homolog 2 (EZH2). Ubiquitination assays and subcellular fractionation further demonstrated that VHL promotes nuclear accumulation of K63-linked ubiquitinated EZH2 (ub-EZH2), leading to proteasome-dependent degradation and reduced EZH2 abundance. Nuclear EZH2 transcriptionally repressed PTEN-induced kinase 1 (PINK1) via trimethylated histone H3 at lysine 27 (H3K27me3), thereby impairing Parkin activation (Ser65 phosphorylation) required for mitophagy. Functionally, FTO destabilized SNHG9 in an m⁶A-YTH domain family protein 2 (YTHDF2)-dependent manner, which restored VHL-mediated EZH2 ubiquitination, reactivated mitophagy, and ultimately reversed CDDP resistance. Importantly, pharmacological m⁶A inhibition and EZH2 degradation effectively suppressed SNHG9 signaling and improved chemosensitivity in preclinical models. Collectively, these findings reveal a previously underappreciated mechanism of CDDP resistance driven by the FTO/SNHG9/VHL/EZH2/PINK1/Parkin axis and support the therapeutic potential of targeting this pathway in LUAD.

PMID:
42600947
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.

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