KDM1 class flavin‐dependent protein lysine demethylases

Abstract

Flavin-dependent, lysine-specific protein demethylases (KDM1s) are a subfamily of amine oxidases that catalyze the selective posttranslational oxidative demethylation of methyllysine side chains within protein and peptide substrates. KDM1s participate in the widespread epigenetic regulation of both normal and disease state transcriptional programs. Their activities are central to various cellular functions, such as hematopoietic and neuronal differentiation, cancer proliferation and metastasis, and viral lytic replication and establishment of latency. Interestingly, KDM1s function as catalytic subunits within complexes with coregulatory molecules that modulate enzymatic activity of the demethylases and coordinate their access to specific substrates at distinct sites within the cell and chromatin. Although several classes of KDM1 -selective small molecule inhibitors have been recently developed, these pan-active site inhibition strategies lack the ability to selectively discriminate between KDM1 activity in specific, and occasionally opposing, functional contexts within these complexes. Here we review the discovery of this class of demethylases, their structures, chemical mechanisms, and specificity. Additionally, we review inhibition of this class of enzymes as well as emerging interactions with coregulatory molecules that regulate demethylase activity in highly specific functional contexts of biological and potential therapeutic importance.

Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni

“…Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that oxidatively cleaves methyl groups from mono and dimethyl Lysine 4 of histone H3 (H3K4me1/2) and can contribute to gene silencing (38)(39)(40)(41). Since its discovery, LSD1 histone demethylase activity has been investigated as a pharmacologic target for cancer and other diseases.…”

Hypoxia favors the generation of human plasma cells

“…[22][23][24][25] In MM, high ANXA2 expression is associated with an adverse prognosis, high-risk proliferation and highrisk gene expression-based signatures. 26 KDM1B is a lysinespecific protein demethylase 27 that functions as an enhancer of gene transcription by modulating H3K4 methylation. 28 Interestingly, KDM1B was shown to control NFkB target gene activation, 29 a pathway playing a critical role in MM survival and proliferation.…”

Knockdown of KDM1A suppresses tumour migration and invasion by epigenetically regulating the TIMP1/MMP9 pathway in papillary thyroid cancer

“…As an important regulator, KDM1A plays critical roles in physiological processes such as the regulation of embryonic development, differentiation shape and identity determination of stem and progenitor cells. It also contributes to a variety of pathological conditions, eg cancer, neuronal disorders and viral infections . Presently, aberrant KDM1A expression is associated with metastasis and unfavourable prognosis in various cancers, suggesting a widespread oncogenic role.…”