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

Dev Cell. 2021 Mar 8;56(5):702-715.e8. doi: 10.1016/j.devcel.2021.01.015. Epub 2021 Feb 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / chemistry
  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Cell Nucleus / pathology*
  • Cell Proliferation
  • Esophageal Neoplasms / genetics
  • Esophageal Neoplasms / metabolism
  • Esophageal Neoplasms / pathology*
  • Esophageal Squamous Cell Carcinoma / genetics
  • Esophageal Squamous Cell Carcinoma / metabolism
  • Esophageal Squamous Cell Carcinoma / pathology*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • RNA, Long Noncoding / chemistry
  • RNA, Long Noncoding / genetics*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • MALAT1 long non-coding RNA, human
  • RNA, Long Noncoding
  • N-methyladenosine
  • Adenosine