LSD1 transcriptome analysis in Merkel cell carcinoma (MCC) cell lines

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cancer of the skin, caused by either excessive UV damage or integration of the Merkel cell polyomavirus (MCV) genome. Here, we report that virally encoded MCV small T antigen (ST) establishes dependence on the LSD1 transcriptional repressor. Inhibition of LSD1 reduces growth of MCV-positive MCC and suppresses ST’s transformation capacity in vitro and in vivo. To define the mechanism of LSD1 inhibition in MCC, we performed a CRISPR loss-of-function library screen. We found that deletion of components of the non-canonical (ncBAF) chromatin remodeler complex confers resistance to LSD1 inhibitors and that LSD1 and ncBAF antagonistically regulate an overlapping set of genes involved in neuron differentiation. Our work provides mechanistic insight into the dependence of MCC on LSD1 and the role of ncBAF as a tumor suppressor in cancer. RNA-seq of six virus-positive (MKL-1, MKL-2, MS-1, WaGa, BroLi and PeTa) and one virus-negative (UISO) MCC cell lines before and after the treatment of specific LSD1 inhibitors for 1 or 3 days.