The protein enzyme SMYD2, an acronym for SET and MYND domain-containing protein 2, functions as a molecular machine that modifies other proteins. Its activities are being studied to better understand both normal cellular function and the development of various diseases, providing insight into the complex regulatory networks that govern cell life.
The Function of SMYD2 as a Methyltransferase
SMYD2 is an enzyme known as a protein-lysine N-methyltransferase, and its primary job is to carry out methylation. This process involves attaching a small chemical tag, a methyl group, to a specific amino acid called lysine on other proteins. This action is similar to adding a sticky note to a document that provides new instructions on how the cell should use it.
The structure of SMYD2 contains regions that allow it to perform this function. The SET domain is the catalytic core responsible for methyltransferase activity. Another part is the MYND domain, a zinc-finger motif that helps the enzyme interact with other proteins, guiding it to its targets. The SET domain is split by the MYND domain, but these sections fold together to create the active site.
SMYD2’s targets are diverse and include both histone and non-histone proteins. Histones are proteins that act like spools for DNA, helping to package genetic material within a cell’s nucleus. By methylating histones, such as histone H3 at lysine 4 (H3K4) or lysine 36 (H3K36), SMYD2 can influence how tightly DNA is wound, regulating which genes are turned on or off. Its ability to methylate non-histone proteins demonstrates its broad influence.
The enzyme’s activity is precise. For example, its ability to trimethylate H3K4 depends on an interaction with a chaperone protein called HSP90alpha, ensuring methylation occurs at the right time and place. The addition of a methyl group to a protein can alter its stability, location, or ability to interact with other molecules, making methylation a fundamental control mechanism.
Involvement in Normal Cellular Processes
In a healthy state, SMYD2 performs housekeeping duties necessary for the body’s normal functions. Its ability to methylate proteins is connected to the regulation of the cell cycle, ensuring that cells divide in an orderly manner. This process is fundamental for the growth and repair of tissues.
The enzyme also contributes to the DNA damage response. When DNA is damaged, response pathways are activated to repair the genetic code. SMYD2 participates in these pathways, helping to maintain the stability of the genome and prevent mutations.
SMYD2 has a recognized role in cell differentiation, particularly in the development of heart and muscle tissues. For instance, studies show SMYD2 is involved in skeletal muscle development in zebrafish. The enzyme is also expressed in tissues like the heart, brain, and kidneys, indicating its broad involvement in multiple organ systems.
The Link Between SMYD2 and Cancer
While SMYD2 is needed for normal cell function, its dysregulation is closely linked to cancer. In many types of cancer, cells exhibit abnormally high levels of SMYD2, a condition known as overexpression. This excess activity disrupts cellular control, contributing to the uncontrolled growth characteristic of cancer.
A primary mechanism through which SMYD2 contributes to cancer is by inactivating tumor suppressor proteins. One of its most significant targets is p53, often called the “guardian of the genome.” p53 monitors cellular stress and DNA damage, halting cell division or initiating cell death to prevent a damaged cell from becoming cancerous. SMYD2 adds a methyl group to p53 at lysine 370, which inhibits its ability to bind to DNA and effectively silences this cellular safety brake.
The consequences of p53 inactivation by SMYD2 allow cancer cells to evade growth controls and resist apoptosis, or programmed cell death. Overexpression of SMYD2 has been documented in a wide array of cancers, including:
- Esophageal squamous cell carcinoma
- Breast cancer
- Bladder cancer
- Liver cancer
- Various leukemias
In many of these cases, higher levels of SMYD2 are correlated with a poorer prognosis for the patient. For example, in studies of esophageal tumors, patients with SMYD2-overexpressing cancers had a worse overall survival rate.
Beyond p53, SMYD2 also targets other tumor suppressors like the retinoblastoma protein (RB) and PTEN, further promoting cancer progression. By methylating RB, SMYD2 can influence cell growth and the DNA damage response, highlighting its multifaceted role in the disease.
Therapeutic Targeting of SMYD2
Given the connection between overactive SMYD2 and cancer, scientists are exploring strategies to block its activity. This has led to the development of SMYD2 inhibitors, which are small-molecule drugs designed to fit into the enzyme’s active site. This prevents it from methylating its protein targets.
The development of these inhibitors is an active area of biomedical research. Compounds like AZ505, BAY-598, and LLY-507 have been created and tested in laboratory settings. Studies show these inhibitors can reduce the proliferation of cancer cells in preclinical models, such as the inhibitor AZ505 reducing tumor growth in models of triple-negative breast cancer.
This therapeutic approach is promising because SMYD2 is often overexpressed in tumor cells compared to normal tissues. This suggests that an inhibitor could selectively target cancer cells with fewer side effects. Combining SMYD2 inhibitors with other treatments, like radiation or other targeted therapies, is also being investigated as a forward-looking avenue for new cancer therapies.