Lysine specific demethylase 1 is a molecular driver and therapeutic target in sarcoma

Abstract

Sarcomas are a diverse group of tumors with numerous oncogenic drivers, and display varied clinical behaviors and prognoses. This complexity makes diagnosis and the development of new and effective treatments challenging. An incomplete understanding of both cell of origin and the biological drivers of sarcomas complicates efforts to develop clinically relevant model systems and find new molecular targets. Notably, the histone lysine specific demethylase 1 (LSD1) is overexpressed in a number of different sarcomas and is a potential therapeutic target in these malignancies. With the ability to modify histone marks, LSD1 is a key player in many protein complexes that epigenetically regulate gene expression. It is a largely context dependent enzyme, having vastly different and often opposing roles depending on the cellular environment and which interaction partners are involved. LSD1 has been implicated in the development of many different types of cancer, but its role in bone and soft tissue sarcomas remains poorly understood. In this review, we compiled what is known about the LSD1 function in various sarcomas, to determine where knowledge is lacking and to find what theme emerge to characterize how LSD1 is a key molecular driver in bone and soft tissue sarcoma. We further discuss the current clinical landscape for the development of LSD1 inhibitors and where sarcomas have been included in early clinical trials.

Keywords: LSD1; epigenetics; mesenchymal development; oncogenic fusion protein; sarcoma.

Figure 1

LSD1 structure and LSD1 containing complexes. (A) Structural illustration of LSD1 in complex with a SANT domain of CoREST or MTA bound to histone H3 tail substrate and cofactor FAD. Essential domains of LSD1 are labeled; tower domain, amine oxidase domain, and the SWIRM domain. (B) LSD1 containing complexes broken down by core interactions and example full complexes.

Figure 2

Schematic of LSD1 mechanism in sarcomas. (A) General mechanism of LSD1 in fusion driven sarcomas. The fusion protein recruits repressor or activator complexes via LSD1 targeting to enact transcriptional deregulation. (B) LSD1 in nonfusion sarcomas demethylates cell cycle check point proteins, inducing cell cycle progression.

Figure 3

Chemical structures of LSD1 inhibitors. Monoamine Oxidase Inhibitors (MAOi); tranylcypromine and pargyline, tranylcypromine derivative irreversible LSD1 inhibitors; GSK2879552, ORY-1001, ORY-2002, IMG7289, INCB059872, combination LSD1 and HDAC inhibitors; JBI-802, Corin, and reversible LSD1 inhibitors; CC-90011, SP-2509, and SP-2577. Images were generated using MolView.