How a cellular regulator becomes a catalyst for cancer development and therapy resistance
Imagine a world where the recycling system in a city suddenly starts working in reverse—instead of breaking down garbage, it carefully retrieves discarded items from trash heaps and returns them to homes and businesses. Soon, the city would become overwhelmed with accumulated junk, systems would fail, and chaos would ensue. This is precisely what happens in our cells when a specialized enzyme called Ubiquitin-Specific Peptidase 37 (USP37) goes rogue in cancer cells.
USP37 functions as a master regulator of protein stability within our cells, determining which proteins should be preserved and which should be discarded.
When this regulation is disrupted, normally short-lived proteins that should be rapidly removed instead accumulate to dangerous levels, driving uncontrolled cell growth and cancer development
To understand USP37's role in cancer, we must first appreciate the elegant recycling system within our cells—the ubiquitin-proteasome pathway. This system acts as the cell's quality control and waste management service, ensuring that proteins are present in the right quantities at the right times.
A small protein called ubiquitin is first activated by an E1 enzyme in an energy-consuming process
An E3 enzyme facilitates transfer of ubiquitin from E2 to specific target proteins, marking them for destruction
Polyubiquitinated proteins are recognized and broken down by the proteasome—the cell's recycling center
This ubiquitin code creates a sophisticated language that controls not only protein destruction but also protein activity, location, and interactions
USP37 belongs to the largest family of deubiquitinating enzymes, known as ubiquitin-specific proteases (USPs), which account for approximately 60% of all human DUBs
USP37 directly controls the G1/S transition—a critical checkpoint determining when a cell commits to division
USP37 stabilizes several powerful cancer-driving proteins (oncogenes), including c-Myc, a transcription factor that promotes cell growth and proliferation
USP37 enhances cancer metastasis—the process by which cancer cells spread to distant organs
| Target Protein | Function in Cancer | Cancer Types Where Identified |
|---|---|---|
| Cyclin A | Drives cell cycle progression | Multiple cancers |
| c-Myc | Promotes cell growth and proliferation | Lung cancer |
| SNAI1 | Triggers epithelial-mesenchymal transition | Breast cancer |
| 14-3-3γ | Activates MAPK signaling pathway | Breast and lung cancers |
| HIF2α | Promotes adaptation to low oxygen | Kidney cancer |
While observational studies had noted USP37 overexpression in various cancers, a pivotal experiment provided direct evidence of its transformative potential. Researchers designed a comprehensive approach to test whether USP37 could directly contribute to tumor formation and progression.
Researchers selected Ba/F3 cells (a murine pro-B cell line) and human cancer cell lines (H1299 lung cancer and MCF7 breast cancer cells) for their experiments
They introduced additional USP37 genes into Ba/F3 cells to overexpress the enzyme and used RNA interference techniques to reduce USP37 levels in cancer cell lines
Ba/F3 cells overexpressing USP37 were subcutaneously transplanted into the flanks of NOD/SCID mice, with a control group receiving mock-transfected cells with normal USP37 levels
Tumor growth was tracked for 6 weeks, with regular measurements of tumor size and volume
Migration assays were performed by creating "wounds" in cell monolayers and measuring closure time; proliferation rates were assessed in cells with altered USP37 expression
The experimental results provided unambiguous evidence of USP37's cancer-promoting functions:
This crucial experiment demonstrated that USP37 isn't merely correlated with cancer but actively drives tumor formation and progression. The stabilization of 14-3-3γ by USP37 emerged as a key mechanism in this process
The implications of these findings are profound: they suggest that inhibiting USP37 could potentially reverse these cancer-promoting effects, providing a rationale for developing USP37-targeted therapies.
The discovery of USP37's multifaceted role in cancer progression has positioned it as an attractive therapeutic target. Several promising approaches are emerging:
Researchers are actively developing small molecule inhibitors that can specifically block USP37's deubiquitinating activity
USP37 is highly expressed in breast cancer stem cells (BCSCs)—cells responsible for tumor initiation and therapy resistance
| Cancer Type | Effect of USP37 Expression | Potential Therapeutic Approach |
|---|---|---|
| Breast Cancer | Confers resistance to cisplatin | USP37 inhibition + chemotherapy |
| Lung Cancer | Stabilizes c-Myc, driving proliferation | USP37 inhibitors alone or in combination |
| Multiple Cancers | Promotes cancer stem cell characteristics | USP37-targeted therapies to prevent recurrence |
Studying a complex enzyme like USP37 requires specialized research tools and reagents. Below are key components of the experimental toolkit that scientists use to unravel USP37's functions:
| Reagent/Technique | Primary Function | Application in USP37 Research |
|---|---|---|
| Co-immunoprecipitation (Co-IP) | Identifies protein-protein interactions | Confirmed USP37 binding to 14-3-3γ and other partners |
| RNA Interference | Reduces specific gene expression | Knocking down USP37 to study functional consequences |
| Glutathione S-Transferase Pull-Down Assays | Tests direct protein interactions | Validated direct binding between USP37 and its targets |
| Ubiquitination Assays | Measures protein ubiquitination status | Demonstrated USP37-mediated deubiquitination of substrates |
| Cell Cycle Synchronization Agents | Halts cells at specific cycle stages | Revealed cell cycle-dependent fluctuation of USP37 |
| NOD/SCID Mice | Immunodeficient animal model | Tested tumor-forming ability of USP37-expressing cells |
The journey to understand Ubiquitin-Specific Peptidase 37 exemplifies how basic scientific research can reveal unexpected insights into human disease. What began as fundamental investigations into protein degradation mechanisms has uncovered a key player in cancer development and progression. USP37 sits at the nexus of multiple cancer-promoting pathways, making it a compelling therapeutic target for future cancer treatments.
Researchers are still working to identify all of USP37's protein substrates and regulatory mechanisms.
The development of specific, potent USP37 inhibitors represents an active area of pharmaceutical research.
As research advances, the hope is that USP37-targeted therapies will join the anticancer arsenal, potentially providing new options for patients with aggressive, treatment-resistant cancers. By understanding and targeting the very mechanisms that cancer cells use to survive and thrive, we move closer to effective strategies for combating this complex disease.