Abstract
Therapeutic options for advanced clear cell renal cell carcinoma (ccRCC) are currently inadequate. Earlier research has shown that the enzyme methyltransferase-like 14 (METTL14) can suppress ccRCC development through the modification of N6-methyladenosine (m6A). This study further explored its complex biological functions and underlying molecular mechanisms. Here, we identified zinc finger protein 14 (ZFP14) as a novel target of METTL14-mediated m6A, and its under-expression was associated with ccRCC tumourigenesis and progression. Detailed investigations revealed that METTL14 interacted directly with the 3' untranslated region of ZFP14 mRNA, promoting m6A modification at two specific sites. These modifications were recognised by the protein insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), which stabilised and enhanced the expression of ZFP14 mRNA. Functionally, the METTL14/ZFP14 axis suppressed in vitro growth, migration and invasiveness and in vivo proliferation and metastasis of ccRCC cells. ZFP14 potentially regulated numbers of transcripts, among which matrix metalloproteinase 1/3 (MMP1/3) were validated to be under-expressed by ZFP14. Crucially, ZFP14 interacted with the signal transducer and activator of transcription 3 (STAT3), augmenting its K48-linked ubiquitination and destabilising it via the proteasome pathway. Moreover, ZFP14 repressed ccRCC cell in vivo growth and metastasis as well as decreasing MMP1/3 levels by under-expressing STAT3. These observations confirmed that ZFP14 served as both a novel target for METTL14-mediated m6A modification and a significant tumour suppressor in ccRCC, shedding light on the cellular and molecular operations in ccRCC and opening up possibilities for novel therapeutic strategies. KEY POINTS: ZFP14 under-expression is associated with ccRCC tumourigenesis and progression. METTL14-mediated m6A enhances ZFP14 mRNA stability and expression with IGF2BP2 as the reader in ccRCC. ZFP14 promotes the degradation of STAT3 by enhancing its K48-linked ubiquitination, inhibiting ccRCC progression.