Harnessing epigenetic regulation to overcome cancer's immune evasion tactics
Multiple myeloma, a cancer of plasma cells in the bone marrow, remains a devastating diagnosis despite significant treatment advances. What makes this cancer particularly challenging is its ability to manipulate the body's own immune defenses, creating a microenvironment where suppressor cells actively protect tumor cells from attack.
Recent research has uncovered an exciting new therapeutic avenue—targeting a specific protein called Histone Deacetylase 6 (HDAC6). Scientists are discovering that inhibiting HDAC6 doesn't just attack cancer cells directly; it also reawakens the immune system, overcoming one of cancer's most sophisticated defense mechanisms.
This article explores how HDAC6 inhibition represents a promising dual-targeting approach in multiple myeloma treatment, simultaneously tackling cancer cells and their protective immune shield.
HDAC6 belongs to a family of enzymes that regulate protein function by removing acetyl groups, but it stands apart from its relatives in several remarkable ways. Unlike other HDACs that primarily work in the cell nucleus controlling gene expression, HDAC6 operates mainly in the cytoplasm where it targets non-histone proteins critical for cell structure, movement, and stress response 9 .
The unique structure of HDAC6 explains its specialized functions. Imagine HDAC6 as a multi-tool with several specialized attachments:
| Domain | Location | Key Functions |
|---|---|---|
| CD1 | N-terminal | Prefers C-terminal acetyllysine substrates; may require CD2 for optimal activity |
| CD2 | Middle section | Main catalytic workhorse; targets α-tubulin, HSP90 with broad specificity |
| ZnF-UBP | C-terminal | Binds ubiquitinated proteins; crucial for aggresome formation |
| SE14 Repeats | Between CD2 and ZnF-UBP | Maintains cytoplasmic localization |
In multiple myeloma, HDAC6 becomes particularly important because of its role in managing cellular stress responses. Cancer cells produce enormous amounts of misfolded proteins, and HDAC6 helps them survive this stress by directing these damaged proteins to cellular disposal systems called aggresomes 4 . This cleaning service becomes a therapeutic vulnerability when combined with proteasome inhibitors—standard multiple myeloma treatments that block an alternative protein disposal route. When both systems are blocked, cancer cells literally choke on their own waste 1 .
While most HDAC6 inhibitors target the catalytic domains, a groundbreaking 2025 study took a different approach—focusing instead on the ZnF-UBP domain 4 . Researchers hypothesized that specifically blocking this domain could disrupt HDAC6's protein-clearance function without affecting its deacetylase activity, potentially offering a more precise therapeutic strategy with fewer side effects.
Using site-directed mutagenesis, they created a dysfunctional ZnF-UBP domain by replacing two critical amino acids (R1155 and Y1156) with alanines—creating what they called the ZnF-UBPRY mutant 4
Through fluorescence polarization assays, they compared the ability of wild-type and mutated domains to bind a ubiquitin-derived peptide 4
Molecular dynamics simulations and electrostatic calculations revealed how the mutation changed the domain's structure and charge properties 4
They introduced the mutated HDAC6 into multiple myeloma cells to observe how the dysfunctional domain affected cancer cell behavior 4
The team designed and synthesized quinazolinylpropanoic acid derivatives as potential therapeutic compounds targeting the ZnF-UBP domain 4
| HDAC6 Modification | Impact on Ubiquitin Binding | Impact on Deacetylase Activity | Effect on Cell Growth |
|---|---|---|---|
| Wild-type HDAC6 | Normal | Normal | Normal growth |
| Complete HDAC6 Deletion | Absent | Absent | Moderately reduced |
| ZnF-UBP Mutation (R1155A-Y1156A) | Abolished | Maintained | Severely reduced |
The findings revealed several crucial insights. The ZnF-UBPRY mutant completely lost its ability to bind ubiquitin, confirming that these two specific residues are essential for HDAC6's interaction with ubiquitinated proteins 4 . Computer models showed the mutation significantly reduced the electrostatic potential of the binding site, diminishing its attraction to ubiquitin.
Most surprisingly, multiple myeloma cells with the dysfunctional ZnF-UBP domain showed more severe impairments than cells completely lacking HDAC6. These engineered cells exhibited reduced cell growth, impaired aggresome formation, and dysregulated gene expression patterns 4 .
This suggested that a partially functional HDAC6 (with catalytic activity but disabled ubiquitin-binding) might be more disruptive to cancer cells than no HDAC6 at all—a phenomenon biologists call a "dominant-negative" effect.
The quinazolinylpropanoic acid derivatives successfully inhibited the ZnF-UBP domain, providing a potential starting point for drug development. This approach could offer therapeutic advantages by specifically blocking HDAC6's role in aggresome formation—a key resistance mechanism in multiple myeloma—while preserving its other functions that might be important for healthy cells 4 .
The immunomodulatory effects of HDAC6 inhibition represent perhaps the most exciting aspect of this research, transforming our understanding of how epigenetic therapies can manipulate the tumor microenvironment.
Multiple myeloma thrives by creating an immunosuppressive environment where certain immune cells protect rather than attack cancer cells. HDAC6 inhibition directly targets these protector cells:
A 2024 study revealed that HDAC6 inhibitors activate proteasomes—cellular complexes that chop up proteins into fragments that can be displayed on the cell surface as "flags" for immune recognition 5 .
When HDAC6 is inhibited, it releases a protein called HR23B that normally interacts with HDAC6's ZnF-UBP domain. Freed HR23B then shuttles more protein fragments to proteasomes, ultimately increasing the diversity and abundance of antigens displayed on multiple myeloma cells 5 .
This expanded antigenic landscape gives the immune system a better chance of recognizing cancer cells as foreign.
| Immune Cell Type | Role in Multiple Myeloma | Effect of HDAC6 Inhibition |
|---|---|---|
| M2 Macrophages | Promote tumor growth, tissue repair, immunosuppression | Suppresses polarization toward M2 phenotype |
| Regulatory T-cells (Tregs) | Suppress antitumor immune responses | Impairs differentiation and suppressive function |
| Cytotoxic T-cells | Directly kill cancer cells | Enhances activation by increasing antigen presentation |
| Dendritic Cells | Present antigens to activate T-cells | Indirectly enhanced through increased antigen availability |
This discovery is particularly significant because it represents a paradigm shift from proteasome inhibition (the mechanism of standard multiple myeloma drugs like bortezomib) to proteasome activation as an anticancer strategy. When researchers treated patient-derived multiple myeloma cells with HDAC6 inhibitors, they observed significantly enhanced ability of autologous CD8+ T-cells to kill cancer cells 5 .
Studying HDAC6 requires specialized tools that allow researchers to dissect its various functions. Here are some essential reagents mentioned in the research:
| Reagent Name | Type | Primary Function in Research |
|---|---|---|
| Tubastatin A | HDAC6 inhibitor | Selective inhibition of HDAC6 deacetylase activity; research standard |
| Ricolinostat (ACY-1215) | HDAC6 inhibitor | Clinical-stage inhibitor; used in translational studies |
| Tubacin | HDAC6 inhibitor | Specifically inhibits α-tubulin deacetylation |
| Quinazolinylpropanoic acid derivatives | ZnF-UBP domain inhibitors | Experimental compounds blocking ubiquitin binding |
| AVS100 | HDAC6 inhibitor | Used in macrophage polarization studies |
| Panobinostat | Pan-HDAC inhibitor | Broad-spectrum inhibitor; reference compound |
| HDAC6 ZnF-UBP peptides | Protein fragments | Study domain-specific interactions without full protein |
| LLVY-R110 substrate | Proteasome activity probe | Measures chymotrypsin-like proteasome activity |
The journey of HDAC6 from basic biological curiosity to promising therapeutic target illustrates how understanding fundamental cellular mechanisms can reveal unexpected therapeutic opportunities. The immunomodulatory effects of HDAC6 inhibition offer a compelling two-pronged attack against multiple myeloma: directly disrupting cancer cell processes while simultaneously reprogramming the immune microenvironment to recognize and eliminate tumor cells.
Early clinical trials have already explored HDAC6 inhibitors like ricolinostat in combination with standard proteasome inhibitors, showing better tolerability than pan-HDAC inhibitors 4 .
Future research will likely shift toward developing drugs that block HDAC6's ubiquitin-binding function without affecting its deacetylase activity, achieving greater precision with fewer side effects 4 .
HDAC6 inhibitors may be paired with immunotherapies to create synergistic effects that fully unleash the immune system against cancer.
The story of HDAC6 inhibition reminds us that sometimes the most effective way to fight cancer isn't just attacking malignant cells directly, but rather reclaiming control of our own immune defenses—reminding them of their original purpose and empowering them to do what they do best: protect us.