Developmental Cell, 20 February, 2021, DOI：https://doi.org/10.1016/j.devcel.2021.01.015

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

Xinyu Wang, Chong Liu, Siwei Zhang, Huiwen Yan, Liwen Zhang, Amin Jiang, Yong Liu, Yun Feng, Di Li, Yuting Guo, Xinyao Hu, Yajing Lin, Pengcheng Bu, Dong Li

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.

Article link：https://linkinghub.elsevier.com/retrieve/pii/S1534580721000733