N6-methyladenosine modification of MALAT1 promotes metastasis via reshaping nuclear speckles

Abstract

N6-methyladenosine (m⁶A), one of the most prevalent RNA post-transcriptional modifications, is involved in numerous biological processes. In previous studies, the functions of m⁶A were typically identified by perturbing the activity of the methyltransferase complex. Here, we dissect the contribution of m⁶A to an individual-long noncoding RNA-metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). The mutant MALAT1 lacking m⁶A-motifs significantly suppressed the metastatic potential of cancer cells both in vitro and in vivo in mouse. Super-resolution imaging showed that the concatenated m⁶A residues on MALAT1 acted as a scaffold for recruiting YTH-domain-containing protein 1 (YTHDC1) to nuclear speckles. We further reveal that the recognition of MALAT1-m⁶A by YTHDC1 played a critical role in maintaining the composition and genomic binding sites of nuclear speckles, which regulate the expression of several key oncogenes. Furthermore, artificially tethering YTHDC1 onto m⁶A-deficient MALAT1 largely rescues the metastatic potential of cancer cells.

Keywords: MALAT1 long noncoding RNA; RNA m(6)A modification; YTHDC1; metastasis; nuclear speckles.