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.

Apoptosis Genes as a Key to Identification of Inverse Comorbidity of Huntington’s Disease and Cancer

“…Selegiline belongs to the class of drugs of monoamine oxidase inhibitors. Its function is preventing monoamine neurotransmitters from breaking down, which are responsible for inhibiting the histone lysine specific demethylase 1, which leads to cancer [64]. Therefore, it is expected to perform efficiently against different types of cancers.…”

The role of VRK1 in chromatin remodeling: regulation of histone post-translational modifications and epigenetic enzymes

“…On the other hand, mutations in TIP60 that inhibit its acetyltransferase activity may impair DNA damage repair mechanisms resulting in genomic instability and leading to carcinogenesis 67 . LSD1 overexpression has been identified in various sarcomas, functioning as oncogenic driver 68 . Furthermore, SUV39H-deficient mice have lower levels of H3K9me3, impairing genomic stability and showing an increased risk of developing cancer 69 .…”

“…KMT2A (or MLL1), the catalytic subunit of the MLL1/MLL complex that mediates methylation of H3K4, directly activates PD-L1 transcription in pancreatic tumor cells 52 . KDM1A (or LSD1) overexpression has been identified in various sarcomas, which makes it an oncogenic driver 68 . KDM4 family proteins (or JMJD2) are highly expressed in several diseases, including breast, gastric, liver and colorectal cancers 236 .…”