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Updated: Nov 19, 2025
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Kinome profiling analysis identified Src pathway as a novel therapeutic target in combination with histone
Nozomi Jimura1, Kazuyasu Fujii1, Zhiwei Qiao2
1Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan; Division of Rare Cancer Research, National Cancer Center Research Institute, Tokyo, Japan.
Background:
Histone deacetylase inhibitors (HDACi) are used to treat patients with cutaneous T-cell lymphoma (CTCL), but they show limited efficacy. Hence, combination therapies should be explored to enhance the effectiveness of HDACis.
Objective:
This study was conducted to identify novel therapeutic targets that can be combined with HDACis for treating CTCL.
Methods:
We performed a global kinome profiling assay of three CTCL cell lines (HH, MJ, and Hut78) with three HDACis (romidepsin, vorinostat, and belinostat) using the PamChip® microarray. The three cell lines were co-treated with romidepsin and an inhibitor against the tyrosine kinase pathway.
Results:
Principal component analysis revealed that kinome expression patterns were mainly related to the cell origin and were not affected by the drugs. Few kinases were commonly activated by the HDACis. Most identified kinases were Src-associated molecules, such as annexin A2, embryonal Fyn-associated substrate, and progesterone receptor. Phosphorylated Src was not observed in any untreated cell lines, whereas Src phosphorylation was detected in two of the three cell lines after HDACi treatment. Ponatinib, a Src inhibitor, significantly enhanced romidepsin-induced apoptosis not only in HH, MJ, and Hut78 cells, but also in Myla and SeAx CTCL cell lines.
Conclusion:
The Src pathway is a possible target for combination therapy involving HDACis for CTCL.
Insights
Combination therapy with histone deacetylase inhibitors (HDACis) can enhance cutaneous T-cell lymphoma (CTCL) treatment. Targeting the Src pathway with inhibitors like ponatinib alongside HDACis shows promise for improving CTCL patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Histone deacetylase inhibitors (HDACis) are a treatment for cutaneous T-cell lymphoma (CTCL).
- Current HDACi efficacy in CTCL is limited, necessitating combination therapies.
- Identifying novel therapeutic targets is crucial for enhancing HDACi effectiveness in CTCL.
Purpose of the Study:
- To discover new therapeutic targets for combination therapy with HDACis in CTCL.
- To investigate the kinome alterations induced by HDACis in CTCL cell lines.
Main Methods:
- Global kinome profiling of three CTCL cell lines (HH, MJ, Hut78) treated with HDACis (romidepsin, vorinostat, belinostat) using PamChip® microarray.
- Co-treatment of CTCL cell lines with romidepsin and a tyrosine kinase pathway inhibitor.
- Assessment of apoptosis induction by combining romidepsin and ponatinib (a Src inhibitor) in multiple CTCL cell lines.
Main Results:
- Kinome expression patterns were primarily cell-line dependent, not significantly altered by HDACis.
- HDACis commonly activated a limited number of kinases, predominantly Src-associated molecules.
- Src phosphorylation was observed after HDACi treatment, and ponatinib significantly enhanced romidepsin-induced apoptosis in various CTCL cell lines.
Conclusions:
- The Src signaling pathway represents a potential target for combination therapy in CTCL.
- Combining Src inhibitors with HDACis may improve therapeutic outcomes for CTCL patients.
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