Epigenetics LSD1 Inhibition

People can think of their genome like a cook book. The instructions are your genetic code, and the finished products are proteins.

Like any recipe, ingredients can be tailored to change the outcome. Your epigenome is responsible helping control the quantity of ingredients without changing your genetic code. Epigenetic illness occurs when the epigenome operates incorrectly or is hijacked.

The field of epigenetics is the study of your epigenome, including the enzymes responsible for regulating the epigenome. Enzymes are special proteins that use chemical reactions to modify DNA and other proteins. Epigenetic enzymes add or remove chemical groups, i.e. epigenetic marks, to chromatin, the structural components of your chromosomes. The location and number of chemical groups on chromatin determine whether the chromatin is “closed”, meaning no gene expression, or “open”, meaning gene expression can begin. This is important because gene expression controls the type and number of proteins that can be found in a cell.

Epigenetic illness occurs when the epigenome operates incorrectly or is hijacked.

Genetic

Cause: Mutated DNA, Read correctly
Requires: Inherited or sporadic mutation
Outcome: Defective Proteins, Cancer

EPIGenetic

Cause: Dysregulated transcription of normal DNA
Requires: Epigenetic Enzymes, Transcription Factors
Outcome: Abnormal protein expression, Cancer

Epigenetic enzymes that remove chemicals are known as “erasers”, and those that add chemicals are known as “writers”.

Writers and erasers are always working to maintain a healthy equilibrium in gene expression patterns. They bind to DNA and work both to “open” and “close” DNA, and to interact with other proteins called transcription factors to initiate gene expression.

In cancer, writers and erasers can do their jobs either too much or too little. Just like too much salt can ruin a meal, the over expression of just one or a handful of proteins can create a tumor in the form of cancer. There is an intimate interplay between the genetic and epigenetic components of DNA, and both are sources of cancer. In the figure above, the top strand illustrates how genetic changes can give rise to cancer via mutations in genes. The bottom strand illustrates how epigenetic changes, proteins binding to DNA to change the way it is read, give rise to cancer via over- or underproduction of proteins. As we learn more about the ramifications of epigenetic changes in cancer pathology, it is becoming clear that targeting the epigenome is a viable strategy for the treatment and management of cancer.

LSD1 Lysine Specific Demethylase (LSD1)

LSD1 is an epigenetic enzyme that can act aberrantly and lead to cancer development and progression. As such, there is a lot of interest to develop drugs that can inhibit LSD1’s activity to treat both solid tumors and hematologic cancers.

Epigenetic Modulator, LSD1 in Cancer

LSD1 has two key functions: 1) demethylation of histone H3 tail and other proteins and 2) act as a scaffolding protein in epigenetic complexes.  The cancer epigenome shows global hypomethylation; LSD1 demethylation at H3K4 and H3K9 is a contributing factor.

LSD1’s demethylation activity removes chemical groups, known as methyl marks, from protein-DNA structures known as nucleosomes. Nucleosomes comprise of DNA wrapped around structural proteins called histones. Histones, like most proteins, contain an amino acid known as lysine, a particularly important amino acid for chemical modification. LSD1 specifically erases methyl marks at lysine 4 and lysine 9 (H3K4, H3K9, “K” is the symbol for lysine). Depending on the presence or absence of methyl marks, DNA assumes an “open” conformation available for transcription of genes, or DNA assumes a “closed” conformation blocking gene expression.

A methyl mark at H3K4 is associated with an open conformation of DNA, and LSD1 closes DNA by removing the methyl mark. In contrast, a methyl mark at H3K9 is associated with a closed conformation of DNA, and LSD1 opens DNA by removing the methyl mark. LSD1 can therefore both promote and block gene expression, and is unique as an epigenetic modifier in this respect. Finally, each lysine can have up to three methyl marks, and LSD1 is only capable of removing the first two marks. The number of methyl marks can also have an effect on gene expression.

Above is an example of how LSD1’s scaffolding properties can drive cancer growth in Ewing sarcoma. (A) LSD1 acts in complex with other proteins, such as the nucleosome remodeling deacetylase complex (NuRD), to inhibit the transcription of tumor suppressor genes. (B) LSD1 can also interact with other proteins (ex: regulator complex) to disrupt the equilibrium of healthy cells and drive expression of a stem cell-like phenotype. This means cells that are differentiated, or designed to perform a tissue-specific function, revert to a more plastic, undefined state characterized by constant growth and invasion of nearby tissues. Seclidemstat inhibits LSD1’s scaffolding properties which (C) allows for the transcription of tumor suppressor genes, and/or (D) prevents transcription relating to self-renewal, and can cause cell apoptosis,  i.e.,death.

In other cancers, LSD1 can associate with various other transcriptional co-activators and co-repressors. For instance, in prostate cancers LSD1 can interact with the androgen receptor to activate genes that drive tumor growth. For this reason, inhibiting LSD1’s demethylation and scaffolding properties is attractive for anti-tumor purposes across various cancer types.