Chromosomal instability-associated MAT1 lncRNA insulates MLL1-guided histone methylation and accelerates tumorigenesis

Cell Rep. 2022 Dec 13;41(11):111829. doi: 10.1016/j.celrep.2022.111829.

Abstract

Acquired chromosomal instability, especially copy number variations (CNVs), has been considered an important determinant of cancer progression and clinical survival. However, the functional role of aberrant CNV-induced lncRNAs in tumorigenesis remains unexplored. Here, we identify a CNV-induced MSC-antisense-transcript 1 (MAT1) lncRNA that plays an oncogenic role in promoting tumorigenesis of uveal melanoma in orthotopic and metastatic xenografts. In addition, our data suggest that MAT1 interrupts the interaction between the MLL1 complex and the PCDH20 promoter by forming an RNA-DNA triplex structure, subsequently abolishing H3K4 trimethylation and inactivating transcription of tumor suppressor PCDH20 to accelerate tumorigenesis. Our data show an intriguing insulation pattern of H3K4 histone modification in tumorigenesis mediated by a lncRNA, thereby providing an alternative mechanism for noncoding blockers in gene regulation.

Keywords: CP: Cancer; MAT1 lncRNA; MLL1 complex; chromosomal instability; tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogenesis / genetics
  • Cell Transformation, Neoplastic / genetics
  • Chromosomal Instability
  • DNA Copy Number Variations
  • Gene Expression Regulation, Neoplastic
  • Histones / metabolism
  • Humans
  • Methylation
  • RNA, Long Noncoding* / genetics
  • RNA, Long Noncoding* / metabolism
  • Uveal Neoplasms* / pathology

Substances

  • RNA, Long Noncoding
  • Histones