Reversion of Merkel cell carcinoma to differentiated neuronal cells using CBP/p300 inhibitors

Summary: Clonally-integrated Merkel cell polyomavirus (MCV) causes Merkel cell carcinoma (MCC) by expression of the T antigen oncogene, which induces Sox2 and Atoh1 transcription factors. Knockdown of T antigen reverses the neuroendocrine phenotype in a keratinocyte co-culture microenvironment model. The cellular histone acetyltransferases CREB-binding protein (CBP) and p300 acetylate histone H3 lysine 18 on the viral T antigen promoter and are required for T antigen expression. Using two different CBP/p300 antagonists with distinct modes of action (A-485 and dCBP-1), we show that CBP/p300 inhibition ablates T antigen expression and promotes tumor cell differentiation of MCC cells with neuron-like neurofilament formations. These cells lose Sox2, Atoh1 and KRT20 expression and the cancer cells undergo cell cycle arrest coupled with expression of the quiescence marker p27kip1. Gene expression analysis revealed downregulation of E2F, MYC target genes, mTORC1 signaling genes, cell cycle associated genes after CBP/p300 inhibition as well as loss of Merkel cell lineage transcription factors and clinical markers. Transcriptomic comparison to a clinical case of clonal combined MCC harboring a cellular component with suppressed T antigen expression and neuroblastic phenotype suggests similar MCC differentiation can contribute to tumor heterogeneity in patients. This is the first example in which small molecule therapy can reverse the transformed cancer phenotype for a human cancer. Kuan Cheok Lei, Mitalee Chandra, Thibault Kevarrec, Hyun Jung Park, Jürgen C. Becker, Masahiro Shuda, Yuan Chang, and Patrick S. Moore