Dual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response.
Donglim Esther ParkJingwei ChengChristian BerriosJoan MonteroMarta Cortés-CrosStéphane FerrettiReety AroraMichelle L TillgrenPrafulla C GokhaleJames A DecaprioPublished in: Proceedings of the National Academy of Sciences of the United States of America (2018)
Merkel cell polyomavirus (MCV) contributes to approximately 80% of all Merkel cell carcinomas (MCCs), a highly aggressive neuroendocrine carcinoma of the skin. MCV-positive MCC expresses small T antigen (ST) and a truncated form of large T antigen (LT) and usually contains wild-type p53 (TP53) and RB (RB1). In contrast, virus-negative MCC contains inactivating mutations in TP53 and RB1. While the MCV-truncated LT can bind and inhibit RB, it does not bind p53. We report here that MCV LT binds to RB, leading to increased levels of ARF, an inhibitor of MDM2, and activation of p53. However, coexpression of ST reduced p53 activation. MCV ST recruits the MYC homologue MYCL (L-Myc) to the EP400 chromatin remodeler complex and transactivates specific target genes. We observed that depletion of EP400 in MCV-positive MCC cell lines led to increased p53 target gene expression. We suspected that the MCV ST-MYCL-EP400 complex could functionally inactivate p53, but the underlying mechanism was not known. Integrated ChIP and RNA-sequencing analysis following EP400 depletion identified MDM2 as well as CK1α, an activator of MDM4, as target genes of the ST-MYCL-EP400 complex. In addition, MCV-positive MCC cells expressed high levels of MDM4. Combining MDM2 inhibitors with lenalidomide targeting CK1α or an MDM4 inhibitor caused synergistic activation of p53, leading to an apoptotic response in MCV-positive MCC cells and MCC-derived xenografts in mice. These results support dual targeting of MDM2 and MDM4 in virus-positive MCC and other p53 wild-type tumors.
Keyphrases
- wild type
- gene expression
- induced apoptosis
- single cell
- transcription factor
- genome wide
- high throughput
- magnetic resonance imaging
- type diabetes
- cell cycle arrest
- stem cells
- immune response
- dna damage
- signaling pathway
- bone marrow
- adipose tissue
- computed tomography
- cell therapy
- mesenchymal stem cells
- high grade
- skeletal muscle
- anti inflammatory
- bioinformatics analysis