LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma

Abstract

Merkel cell carcinoma (MCC) is a highly aggressive, neuroendocrine skin cancer that lacks actionable mutations, which could be utilized for targeted therapies. Epigenetic regulators governing cell identity may represent unexplored therapeutic entry points. Here, we targeted epigenetic regulators in a pharmacological screen and discovered that the lysine‐specific histone demethylase 1A (LSD1/KDM1A) is required for MCC growth in vitro and in vivo. We show that LSD1 inhibition in MCC disrupts the LSD1‐CoREST complex leading to displacement and degradation of HMG20B (BRAF35), a poorly characterized complex member that is essential for MCC proliferation. Inhibition of LSD1 causes derepression of transcriptional master regulators of the neuronal lineage, activates a gene expression signature resembling normal Merkel cells, and induces cell cycle arrest and cell death. Our study unveils the importance of LSD1 for maintaining cellular plasticity and proliferation in MCC. There is also growing evidence that cancer cells exploit cellular plasticity and dedifferentiation programs to evade destruction by the immune system. The combination of LSD1 inhibitors with checkpoint inhibitors may thus represent a promising treatment strategy for MCC patients.

Role of Virus-Induced Host Cell Epigenetic Changes in Cancer

“…Inhibition of KDM1A with the drug GSK-LSD1 induced growth arrest and cell death of several MCPyV positive MCC cell lines and significantly reduced tumor growth in a xenograft model compared with vehicle treated animals. No synergistic effect was observed when HDAC and LSD1 inhibitors were used [ 381 ].…”

Viral Manipulation of the Host Epigenome as a Driver of Virus-Induced Oncogenesis

“…Recently, LSD1 inhibition showed to be promising in the treatment of MCC. Specifically, LSD1 inhibitors negatively impact Merkel carcinoma cell growth in vitro and in vivo by promoting their differentiation toward normal Merkel cell fate [222,402,403]. Moreover, LSD1 inhibition sensitized hepatocellular carcinoma cells to sorafenib and regorafenib [404,405].…”

Epigenetic regulation and signalling pathways in Merkel cell development

“…functions together with the CoREST repressor complex and competes with the Merkel cell master regulator ATOH1 to represses the normal transcriptional programme. 222,223 Pharmacological inhibition or silencing of LSD1 impairs MCC cell proliferation and tumorigenic properties, and upregulates the transcriptional signature of normal Merkel cells. 222,223 However, whether LSD1-CoREST or other epigenetic regulators play a role in Merkel cell development is yet to be determined.…”

“…222,223 Pharmacological inhibition or silencing of LSD1 impairs MCC cell proliferation and tumorigenic properties, and upregulates the transcriptional signature of normal Merkel cells. 222,223 However, whether LSD1-CoREST or other epigenetic regulators play a role in Merkel cell development is yet to be determined. Understating the mechanisms controlling Merkel cell biology will not only pave the way for devising strategies to engineer epidermis with both barrier and sensory functions for skin replacement in patients with blistering skin diseases or chronic wounds, [224][225][226] but will also enable a better understanding of human pathologies such as Merkel cell carcinoma.…”