GSE134898
A cancer-specific ubiquitin ligase drives alternative polyadenylation by targeting PCF11
Alternative polyadenylation (APA) contributes to the complexity of the transcriptome by generating mRNA isoforms with varying 3' UTR lengths. APA leading to 3' UTR shortening (3'-US) of mRNAs is a common feature of most cancer cells. However, the molecular mechanisms promoting APA in cancer are not well established. Here, we describe a widespread mechanism promoting 3'-US in cancer through ubiquitination and degradation of the 3' 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 human 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 for degradation. This leads to APA of many transcripts in ovarian and lung tumors from both mouse xenografts and human tumor specimens. Importantly, expression of a non-degradable PCF11 degron mutant suppressed MAGE-A11 oncogenic activity and 3'-US. Analysis of the transcripts affected by MAGE-A11, revealed core oncogenic and tumor suppressor genes and pathways. This includes 3'-US of the cyclin D2 oncogene leading to deregulation of the Rb tumor suppressor pathway. Furthermore, competing endogenous RNA (ceRNA) partners of 3'-US transcripts include many tumor suppressor genes, such as PTEN that is downregulated by MAGE-A11 resulting in activation of the Akt growth signaling pathway. These findings provide insights into the function of MAGE-A11 and help explain the molecular mechanisms driving APA in cancer. Overall design: Examination of alternative polyadenylation and gene expression upon MAGEA11 expression in HEK293FT, DAOY, A2780, and OV56 cells.