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Pharmacologic reversion of Merkel cell carcinoma via CBP/p300 inhibition
Joseph L Collura1, Kuan Cheok Lei2,3, Mitalee Chandra2
1Cancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA 15213.
Abstract:
Merkel cell polyomavirus (MCV) T antigen functions as an oncoprotein that drives the transformation of Merkel cell carcinoma (MCC) cells by activating transcription factors involved in cell proliferation. The viral T antigen promoter requires the activity of the cellular coactivator CREB-binding protein (CBP)/p300 for its expression. Inhibition of CBP/p300 with two distinct small-molecule inhibitors suppresses T antigen expression, leading to cell cycle arrest and upregulation of the cell cycle inhibitor p27Kip1. This shift promotes neuronal differentiation, associated with neurite outgrowth in MCC cells. RNA sequencing revealed downregulation of genes involved in E2F, Myc, mTORC1 oncogenic signaling, as well as markers of the Merkel cell lineage including Sox2 and Atoh1. Notably, a rare MCC case exhibiting a mixed cellular composition, with loss of T antigen expression and neuroblastic phenotype, showed a transcriptomic profile resembling that of MCC cells treated with CBP/p300 inhibitors. This suggests that similar differentiation processes may contribute to tumor heterogeneity in patients. This study presents the model system enabling reversible switching between a transformed and differentiated cell state in a human cancer using small-molecule treatment.
Insights
Small molecules targeting CREB-binding protein (CBP)/p300 inhibit Merkel cell carcinoma (MCC) by suppressing viral oncoprotein expression. This induces cell cycle arrest and promotes neuronal differentiation, offering a novel therapeutic strategy for MCC.
Area of Science:
- Oncology
- Virology
- Cell Biology
Background:
- Merkel cell polyomavirus (MCV) T antigen drives Merkel cell carcinoma (MCC) through oncogenic signaling.
- Viral T antigen expression depends on the cellular coactivator CREB-binding protein (CBP)/p300.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting CBP/p300 in MCC.
- To elucidate the mechanisms underlying MCC cell transformation and differentiation.
Main Methods:
- Treatment of MCC cells with small-molecule inhibitors of CBP/p300.
- RNA sequencing to analyze gene expression changes.
- Analysis of a rare MCC case with mixed cellular composition.
Main Results:
- CBP/p300 inhibition suppressed T antigen expression, induced cell cycle arrest, and promoted neuronal differentiation.
- Downregulation of E2F, Myc, and mTORC1 oncogenic pathways observed.
- Transcriptomic profile of a rare MCC case mirrored inhibitor-treated cells, suggesting differentiation contributes to tumor heterogeneity.
Conclusions:
- Targeting CBP/p300 offers a strategy to reverse MCC cell transformation and induce differentiation.
- Tumor heterogeneity in MCC may be partly driven by differentiation processes.
- A model system for reversible switching between transformed and differentiated states in cancer was established.
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