The WW domain presents a promising target for the development of PCIF1 agonists in the treatment of glioma.

PCIF1 is currently the sole m6Am methyltransferase in mammalian mRNA, but it was initially named for the interaction between its WW domain and RNA polymerase II. Emerging studies reveal the important role of PCIF1 in the progression of various cancers, particularly highlighting its methyltransferase activity. Recently, we found that PCIF1 effectively inhibited the growth of gliomas both in vitro and in vivo. Notably, this inhibition was not entirely dependent on its methyltransferase activity. In this study, we found that the deletion or mutation of the WW domain reversed the inhibitory effect of PCIF1 on cell proliferation in both PCIF1 wild-type and knockout glioma cells. Overexpression of the WW domain of PCIF1 alone significantly inhibited glioma cell proliferation without notable effects on normal astrocytes, and this inhibition was more pronounced when the WW domain was localized to the nucleus. Introduction of an exogenous WW domain reduced PCIF1 protein stability, subsequently diminishing its interaction with RNA Polymerase II. Mechanistically, forced expression of the WW domain into the nucleus facilitated the translocation of endogenous PCIF1 from the nucleus to the cytoplasm and promoted its degradation through the ubiquitin-proteasome system and the autophagy-lysosomal pathway. In addition, overexpression of the WW domain of PCIF1 inhibited the growth of gliomas and extended the survival of tumor-bearing mice. These data indicate that the WW domain plays a crucial role in PCIF1-mediated inhibition of glioma cell growth and presents a promising target for the development of PCIF1 agonists in glioma treatment.