UBR5 Is Coamplified with MYC in Breast Tumors and Encodes an Ubiquitin Ligase That Limits MYC-Dependent Apoptosis

Xi Qiao, Ying Liu, Maria Llamazares Prada, Aravind K. Mohan, Abhishekh Gupta, Alok Jaiswal, Mukund Sharma, Joni Merisaari, Heidi M Haikala, Kati Talvinen, Laxman Yetukuri, Joanna W. Pylvänäinen, Juha Klefström, Pauliina Kronqvist, Annika Meinander, Tero Aittokallio, Ville Hietakangas, Martin Eilers, Jukka Westermarck

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Abstract

For maximal oncogenic activity, cellular MYC protein levels need to be tightly controlled so that they do not induce apoptosis. Here, we show how ubiquitin ligase UBR5 functions as a molecular rheostat to prevent excess accumulation of MYC protein. UBR5 ubiquitinates MYC and its effects on MYC protein stability are independent of FBXW7. Silencing of endogenous UBR5 induced MYC protein expression and regulated MYC target genes. Consistent with the tumor suppressor function of UBR5 (HYD) in Drosophila, HYD suppressed dMYC-dependent overgrowth of wing imaginal discs. In contrast, in cancer cells, UBR5 suppressed MYC-dependent priming to therapy-induced apoptosis. Of direct cancer relevance, MYC and UBR5 genes were coamplified in MYC-driven human cancers. Functionally, UBR5 suppressed MYC-mediated apoptosis in p53-mutant breast cancer cells with UBR5/MYC coamplification. Furthermore, single-cell immunofluorescence analysis demonstrated reciprocal expression of UBR5 and MYC in human basal-type breast cancer tissues. In summary, UBR5 is a novel MYC ubiquitin ligase and an endogenous rheostat for MYC activity. In MYC-amplified, and p53-mutant breast cancer cells, UBR5 has an important role in suppressing MYC-mediated apoptosis priming and in protection from drug-induced apoptosis. SIGNIFICANCE: These findings identify UBR5 as a novel MYC regulator, the inactivation of which could be very important for understanding of MYC dysregulation on cancer cells. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/7/1414/F1.large.jpg.

Original languageEnglish
Pages (from-to)1414-1427
Number of pages14
JournalCancer Research
Volume80
Issue number7
DOIs
Publication statusPublished - Apr 2020
MoE publication typeA1 Journal article-refereed

Keywords

  • Animals
  • Animals, Genetically Modified
  • Apoptosis/genetics
  • Breast/pathology
  • Breast Neoplasms/genetics
  • Cell Line, Tumor
  • DNA-Binding Proteins/genetics
  • Drosophila Proteins/genetics
  • Female
  • Gene Amplification
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kaplan-Meier Estimate
  • Models, Animal
  • Protein Stability
  • Proto-Oncogene Proteins c-myc/genetics
  • RNA-Seq
  • Tissue Array Analysis
  • Transcription Factors/genetics
  • Ubiquitin-Protein Ligases/genetics
  • Ubiquitination/genetics

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