A Cancer-Specific Ubiquitin Ligase Drives mRNA Alternative Polyadenylation by Ubiquitinating the mRNA 3' End Processing Complex

Mol Cell. 2020 Mar 19;77(6):1206-1221.e7. doi: 10.1016/j.molcel.2019.12.022. Epub 2020 Jan 21.

Abstract

Alternative polyadenylation (APA) contributes to transcriptome complexity by generating mRNA isoforms with varying 3' UTR lengths. APA leading to 3' UTR shortening (3' US) is a common feature of most cancer cells; however, the molecular mechanisms are not understood. Here, we describe a widespread mechanism promoting 3' US in cancer through ubiquitination of the mRNA 3' end processing complex protein, PCF11, by the cancer-specific MAGE-A11-HUWE1 ubiquitin ligase. MAGE-A11 is normally expressed only in the male germline but is frequently re-activated in cancers. MAGE-A11 is necessary for cancer cell viability and is sufficient to drive tumorigenesis. Screening for targets of MAGE-A11 revealed that it ubiquitinates PCF11, resulting in loss of CFIm25 from the mRNA 3' end processing complex. This leads to APA of many transcripts affecting core oncogenic and tumor suppressors, including cyclin D2 and PTEN. These findings provide insights into the molecular mechanisms driving APA in cancer and suggest therapeutic strategies.

Keywords: 3′ UTR shortening; 3′ end processing complex; CFIm25; HUWE1; MAGE-A11; PCF11; PTEN; alternative polyadenylation; cyclin D2; ubiquitin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics*
  • Animals
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / metabolism*
  • Apoptosis
  • Biomarkers, Tumor
  • Carcinogenesis
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cell Proliferation
  • Cleavage And Polyadenylation Specificity Factor / genetics
  • Cleavage And Polyadenylation Specificity Factor / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Polyadenylation
  • RNA Splicing
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination
  • Xenograft Model Antitumor Assays
  • mRNA Cleavage and Polyadenylation Factors / genetics
  • mRNA Cleavage and Polyadenylation Factors / metabolism*

Substances

  • 3' Untranslated Regions
  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • Cleavage And Polyadenylation Specificity Factor
  • MAGEA11 protein, human
  • Neoplasm Proteins
  • Nudt21 protein, human
  • Pcf11 protein, human
  • RNA, Messenger
  • Tumor Suppressor Proteins
  • Ubiquitin
  • mRNA Cleavage and Polyadenylation Factors
  • HUWE1 protein, human
  • Ubiquitin-Protein Ligases