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Class IIa HDAC inhibition enhances ER stress-mediated cell death in multiple myeloma
S Kikuchi1, R Suzuki1, H Ohguchi1
1Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Abstract:
Histone deacetylase (HDAC) inhibitors have been extensively investigated as therapeutic agents in cancer. However, the biological role of class IIa HDACs (HDAC4, 5, 7 and 9) in cancer cells, including multiple myeloma (MM), remains unclear. Recent studies show HDAC4 interacts with activating transcription factor 4 (ATF4) and inhibits activation of endoplasmic reticulum (ER) stress-associated proapoptotic transcription factor C/EBP homologous protein (CHOP). In this study, we hypothesized that HDAC4 knockdown and/or inhibition could enhance apoptosis in MM cells under ER stress condition by upregulating ATF4, followed by CHOP. HDAC4 knockdown showed modest cell growth inhibition; however, it markedly enhanced cytotoxicity induced by either tunicamycin or carfilzomib (CFZ), associated with upregulating ATF4 and CHOP. For pharmacological inhibition of HDAC4, we employed a novel and selective class IIa HDAC inhibitor TMP269, alone and in combination with CFZ. As with HDAC4 knockdown, TMP269 significantly enhanced cytotoxicity induced by CFZ in MM cell lines, upregulating ATF4 and CHOP and inducing apoptosis. Conversely, enhanced cytotoxicity was abrogated by ATF4 knockdown, confirming that ATF4 has a pivotal role mediating cytotoxicity in this setting. These results provide the rationale for novel treatment strategies combining class IIa HDAC inhibitors with ER stressors, including proteasome inhibitors, to improve patient outcome in MM.
Insights
Targeting HDAC4 in multiple myeloma (MM) enhances cancer cell death under endoplasmic reticulum (ER) stress. Inhibiting HDAC4, alongside proteasome inhibitors like carfilzomib, offers a promising strategy to improve MM treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Histone deacetylase (HDAC) inhibitors are explored for cancer therapy.
- The role of class IIa HDACs, including HDAC4, in multiple myeloma (MM) is not well understood.
- HDAC4 is known to interact with ATF4 and suppress ER stress-induced apoptosis via CHOP.
Purpose of the Study:
- To investigate the role of HDAC4 in MM cells under ER stress.
- To determine if HDAC4 inhibition enhances apoptosis in MM cells.
- To explore the therapeutic potential of combining class IIa HDAC inhibitors with ER stressors.
Main Methods:
- HDAC4 knockdown was performed in MM cells.
- Cells were treated with ER stressors (tunicamycin) or proteasome inhibitors (carfilzomib).
- A selective class IIa HDAC inhibitor (TMP269) was used for pharmacological inhibition, alone and with carfilzomib.
- The expression of ATF4 and CHOP was analyzed.
- ATF4 knockdown was used to confirm its role.
Main Results:
- HDAC4 knockdown modestly inhibited MM cell growth but significantly enhanced cytotoxicity induced by tunicamycin or carfilzomib.
- HDAC4 knockdown led to increased levels of ATF4 and CHOP.
- Pharmacological inhibition of HDAC4 with TMP269 also enhanced carfilzomib-induced cytotoxicity, upregulating ATF4 and CHOP.
- The enhanced cytotoxicity was dependent on ATF4, as ATF4 knockdown abrogated this effect.
- Apoptosis was significantly induced in MM cells under these conditions.
Conclusions:
- HDAC4 plays a crucial role in regulating apoptosis in MM cells under ER stress.
- Combining class IIa HDAC inhibitors with ER stressors, such as proteasome inhibitors, can effectively enhance anti-myeloma activity.
- This combination strategy holds promise for improving treatment outcomes in multiple myeloma patients.
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