N⁶-Methyladenosine Regulates Cilia Elongation in Cancer Cells by Modulating HDAC6 Expression

Primary cilia are microtubule-based organelles that function as cellular antennae to address multiple metabolic and extracellular cues. The past decade has seen significant advances in understanding the pro-tumorigenic role of N⁶-methyladenosine (m⁶A) modification in tumorigenesis. Nevertheless, whether m⁶A modification modulates the cilia dynamics during cancer progression remains unclear. Here, the results show that m⁶A methyltransferase METTL3 regulates cilia length in cancer cells via HDAC6-dependent deacetylation of axonemal α-tubulin, thereby controlling cancer development. Mechanically, METTL3 positively regulates the translation of HDAC6 in an m⁶A-dependent manner, while m⁶A methylation of A3678 in the coding sequence (CDS) of HDAC6 ameliorates its translation efficiency via facilitating the binding with YTHDF3. The upregulation of HDAC6 induced by METTL3 over-expression is capable of inhibiting cilia elongation and acetylation of α-tubulin, thereby shortening cilia length and accelerating the progression of cervical cancer both in vitro and in vivo. Collectively, depletion of METTL3-mediated m⁶A modification leads to abnormally elongated cilia via suppressing HDAC6-dependent deacetylation of axonemal α-tubulin, ultimately attenuating cell growth and cervical cancer development.