Lysine-specific demethylase 1 (LSD1), also known as KDM1A, is an enzyme discovered in 2004 that manages how our genes are used. It influences whether specific genes are turned on or off within cells. As the first identified enzyme capable of removing methyl groups from proteins, LSD1 has advanced our understanding of gene expression control. Its actions help regulate processes that determine cell function and identity.
How LSD1 Regulates Genes
Our genetic information, DNA, is tightly wound around proteins called histones, forming chromatin. This packaging influences how accessible genes are for reading. LSD1 functions as a demethylase, an enzyme that removes methyl groups from specific lysine residues on histone H3, particularly at positions 4 (H3K4) and 9 (H3K9). This process is part of epigenetics, modifications to DNA and associated proteins that affect gene activity without altering the DNA sequence.
LSD1 removes these methyl groups through an oxidative reaction, using flavin-adenine dinucleotide (FAD) as a cofactor. This reaction produces the demethylated lysine. Depending on the specific histone lysine modified and the protein complexes LSD1 associates with, this demethylation can lead to either gene activation or repression. For instance, LSD1 often partners with the CoREST complex to remove methyl groups from H3K4, which silences gene expression.
Conversely, LSD1 can remove methyl groups from H3K9, which can activate transcription when it interacts with specific receptors like the androgen receptor. This dual capacity highlights LSD1’s adaptability in controlling gene activity. The enzyme’s ability to modify histone marks makes it a player in genome regulation, influencing how genetic instructions are interpreted.
LSD1’s Function in Healthy Cells
In healthy individuals, LSD1 performs various functions important for normal biological processes. It contributes to embryonic development, guiding how a single fertilized egg develops into a complex organism. LSD1 also influences cell differentiation, the process by which immature stem cells mature into specialized cell types like nerve cells or blood cells. For example, it helps regulate the balance between self-renewal and differentiation in embryonic stem cells.
LSD1 is involved in maintaining the proper function of hematopoietic stem cells, which produce all types of blood cells. Its activity helps regulate the differentiation pathways of these cells, ensuring the correct balance of cell types. The enzyme also contributes to metabolic balance, with studies suggesting its involvement in processes like adipogenesis, the formation of fat cells.
Beyond histones, LSD1 also removes methyl groups from non-histone proteins, such as p53 and DNMT1. This broad substrate specificity allows LSD1 to participate in a wide array of normal physiological processes, from cell proliferation and chromosome segregation to maintaining the epigenome’s integrity by influencing DNA methylation levels.
The Connection Between LSD1 and Cancer
While LSD1 plays a normal role in healthy cells, its activity can become dysregulated, contributing to cancer development and progression. In many cancer types, LSD1 is found in abnormally high amounts, or its activity is altered. This overexpression has been observed in various malignancies, including acute myeloid leukemia (AML), neuroblastoma, prostate cancer, breast cancer, small cell lung cancer, and gastric cancer. Such elevated levels of LSD1 are often associated with a less favorable prognosis.
The problematic role of LSD1 in cancer often stems from its ability to inappropriately silence tumor suppressor genes. By removing methyl marks that would normally allow these protective genes to be active, LSD1 can effectively “turn off” the body’s natural defenses against cancer growth. For example, LSD1 can reduce the activity of the tumor suppressor p53, preventing programmed cell death and enabling cancer cells to survive and multiply unchecked.
Conversely, LSD1 can also activate genes that promote cancer cell growth and survival, known as oncogenes. This dual action allows cancer cells to proliferate more rapidly, resist chemotherapy drugs, and develop the ability to spread to other parts of the body, a process called metastasis. The enzyme’s involvement in processes like epithelial-mesenchymal transition (EMT) is linked to increased cancer cell invasiveness.
Targeting LSD1 for Medical Treatment
Recognizing LSD1’s involvement in cancer, scientists are exploring strategies to target this enzyme for medical treatment. A promising approach involves developing LSD1 inhibitors, drugs designed to block the enzyme’s activity. These inhibitors work by preventing LSD1 from removing methyl groups from histones and other proteins, aiming to restore normal gene expression patterns. This can potentially reactivate silenced tumor suppressor genes or suppress cancer-promoting genes.
LSD1 inhibitors can be broadly categorized as covalent or non-covalent, referring to how they bind to and inhibit the enzyme. Several inhibitors, including iadademstat (ORY-1001), bomedemstat (IMG-7289), GSK-2879552, and pulrodemstat (CC-90011), are currently undergoing clinical trials for various cancers. These trials are investigating their effectiveness in treating conditions like acute myeloid leukemia and small cell lung cancer.
The goal of LSD1 inhibition in cancer therapy is often to induce differentiation in cancer cells, forcing them to mature and lose their ability to divide uncontrollably. Some studies also explore combining LSD1 inhibitors with other therapies, such as all-trans-retinoic acid (ATRA) for AML, or with immune checkpoint inhibitors, to enhance treatment effectiveness. This research focuses on developing new cancer treatments that target epigenetic mechanisms.