NSD2 is a gene that produces a protein known as Nuclear Receptor Binding SET Domain Protein 2. This protein is present in many of the body’s cells and tissues, both before and after birth, suggesting a fundamental role in biological processes.
Understanding NSD2 and Its Normal Role
The NSD2 gene provides instructions for creating proteins like MMSET I, MMSET II, and RE-IIBP. These proteins are involved in normal development and help regulate the activity of other genes. NSD2 functions as a histone methyltransferase, an enzyme that modifies proteins called histones.
Histones are like spools around which DNA is wound, forming chromatin. Histone methylation is the process of adding a methyl group to these histone proteins, particularly to lysine 36 of histone H3 (H3K36). This modification influences how tightly DNA is packed, affecting whether genes are turned on or off. NSD2 can suppress or activate certain genes, playing a role in epigenetics, which studies how gene expression is regulated without altering the underlying DNA sequence. NSD2 also contributes to maintaining chromatin integrity and regulating genes involved in cell division, programmed cell death, and DNA repair.
NSD2’s Connection to Disease
When the NSD2 gene or its protein functions abnormally, it can contribute to various diseases. A significant connection exists with multiple myeloma, a cancer originating in bone marrow plasma cells. This cancer frequently involves a chromosomal rearrangement, or translocation, where part of chromosome 4, containing the NSD2 gene, fuses with a gene on chromosome 14. This specific translocation, t(4;14)(p16.3;q32), is found in 15% to 20% of all multiple myeloma cases and leads to NSD2 gene overexpression.
Overexpression of NSD2 in multiple myeloma promotes the uncontrolled growth and division of cancer cells. It does this by altering how DNA is folded and how genes are switched on or off, particularly those that help cancer cells maintain their identity as plasma cells. Overactive NSD2 increases H3K36me2, a specific histone modification, which can lead to the aberrant activation of genes related to cell adhesion, proliferation, and cancer development. Beyond multiple myeloma, NSD2 dysregulation has been observed in various solid tumors, including lung, prostate, colorectal, cervical, breast, and osteosarcoma, often correlating with unfavorable prognoses and promoting cell proliferation, migration, and invasion.
Therapeutic Approaches Targeting NSD2
The understanding of NSD2’s role in disease, especially cancer, has led to research into therapeutic strategies that specifically target this protein. One promising approach involves developing NSD2 inhibitors, compounds designed to block the enzyme’s methyltransferase activity. By inhibiting NSD2, these compounds aim to reverse abnormal histone methylation patterns, potentially reactivating tumor suppressor genes and making cancer cells more susceptible to other treatments.
These inhibitors are being explored for their effectiveness in various cancers, including acute lymphoblastic leukemia and several solid tumors where NSD2 dysregulation is implicated in disease progression. The concept of precision medicine aligns well with targeting NSD2, as it allows for treatments tailored to patients whose cancers exhibit NSD2 abnormalities, such as the t(4;14) translocation in multiple myeloma. While many NSD2 inhibitors are in early stages of drug development, some, like KTX-1001, are already in Phase I clinical trials for relapsed and refractory multiple myeloma. Future directions include investigating combination therapies that pair NSD2 inhibitors with other anti-cancer agents to maximize therapeutic benefits and overcome drug resistance.