How tiny protein regulators in our cells hold the key to new cancer treatments
Within every cell in our body, a meticulous cleanup process is constantly underway. Proteins that have served their purpose or become damaged are tagged for disposal, ensuring the smooth operation of cellular life. A critical family of proteins, the Kelch-like (KLHL) family, serves as the dedicated crew in charge of this process. They are the recognition specialists, pinpointing which proteins need to be removed. When this delicate system breaks down, the consequences can be dire. Recent research reveals that the dysregulation of KLHL proteins is a key step on the path to cancer, making this family of molecules a promising new frontier in the fight against the disease 2 6 .
KLHL proteins function as the cellular cleanup crew, identifying proteins for destruction. When this system fails, it can lead to cancer development.
To understand their role in cancer, we must first understand what KLHL proteins do in healthy cells.
KLHL proteins are crucial components of the ubiquitin-proteasome system, the cell's primary protein degradation pathway 2 . Think of it as a highly specific recycling center.
Ubiquitin is activated by E1 enzyme
Ubiquitin is transferred to E2 enzyme
KLHL (E3) recognizes target and facilitates ubiquitin transfer
Once a protein is marked with a chain of ubiquitin molecules, it is directed to the proteasome, a cellular structure that chops it into tiny pieces for reuse 2 .
KLHL proteins function as the substrate-recognizing subunits for a major class of E3 ligases called Cullin-RING ligase 3 (CRL3) complexes 2 6 . Their structure is perfectly designed for this job:
Binds to the Cullin-3 scaffold protein
Acts as a bridge between the other two domains
Forms a propeller-like structure that specifically recognizes and binds to target proteins
By recruiting specific substrates to the CRL3 machinery, KLHL proteins directly control the levels of numerous other proteins involved in critical processes like cell growth, stress response, and cell death 6 . When a KLHL protein is lost or mutated, its specific substrates are no longer properly degraded. They accumulate in the cell, which can drive uncontrolled growth—a hallmark of cancer.
To illustrate the cancer connection, let's examine a key experiment that uncovered the role of KLHL5 in colorectal cancer (CRC).
A comprehensive 2025 study set out to identify which of the 42 KLHL family members are most critical in colorectal cancer 1 4 .
Researchers started by analyzing transcriptome data from The Cancer Genome Atlas (TCGA) colorectal adenocarcinoma cohort. They sifted through the expression data of all 42 KLHL genes, looking for those that were both highly expressed and showed significant variation among patients. From this analysis, KLHL5 emerged as a top candidate for further investigation 4 .
The findings were striking and consistently pointed to KLHL5 as a key player in cancer aggression.
| Association Between High KLHL5 Expression and Clinicopathological Features in Colorectal Cancer 1 | |
|---|---|
| Clinicopathological Feature | Statistical Significance (p-value) |
| Depth of Invasion | p < 0.001 |
| Lymph Node Metastasis | p = 0.025 |
| Lymphovascular Invasion | p = 0.029 |
| Advanced Cancer Stage (I to IV) | p < 0.05 |
The story of KLHL5 is just one example. The dysfunction of various KLHL family members is being uncovered in a wide spectrum of cancers, each regulating different cancer-relevant substrates.
| Examples of KLHL Family Members in Human Cancers 2 7 8 | ||
|---|---|---|
| KLHL Protein | Related Cancers | Key Substrate(s) & Proposed Role |
| KLHL19 (KEAP1) | Pancreatic, Gastric, Colorectal | Degrades NRF2; mutations lead to oxidative stress resistance and tumor growth 8 . |
| KLHL17 | Pancreatic | Regulates vimentin and nestin; associated with inflammation and cancer risk 7 . |
| KLHL21 | Cholangiocarcinoma, Liver | High expression linked to unfavorable patient outcomes 8 . |
| KLHL22 | Colorectal | Low expression reported in tumors, suggesting a potential tumor-suppressive role 8 . |
When overexpressed, these KLHL proteins promote cancer progression by degrading tumor suppressor proteins.
When lost or mutated, these KLHL proteins fail to degrade oncoproteins, allowing cancer to develop.
Studying this complex protein family requires a sophisticated set of tools. The following reagents and methods are essential for uncovering the roles of KLHLs in cancer biology.
Used in techniques like immunohistochemistry (IHC) and Western blotting to visualize and measure KLHL proteins 4 .
Allows precise knockout or modification of KLHL genes to determine functional consequences 7 .
Studies genetic variants to reveal how they affect transcription factor binding 7 .
The journey into the world of KLHL proteins demonstrates how fundamental cellular housekeeping is inextricably linked to human health. As we have seen with KLHL5 in colorectal cancer, when these meticulous regulators of protein stability are disrupted, the balance tips toward malignancy 1 4 .
For KLHLs like KLHL5 that are overexpressed and drive cancer progression, drugs that inhibit their activity could restore the degradation of harmful proteins 8 .
For tumor-suppressive KLHLs that are lost, strategies to reactivate or replace their function could be transformative.