Contribution of STAT3 and RAD23B in Primary Sézary Cells to Histone Deacetylase Inhibitor FK228 Resistance
| Autor: | Maria Demontis, Silvia A. Ferreira, Rosie M. Butler, Christine L. Jones, Tracey J. Mitchell, Isabella Tosi, Charlotte E. Flanagan, Robert C.T. McKenzie, Wesley J. Woollard, Sean Whittaker, Susan D. John |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
CD4-Positive T-Lymphocytes STAT3 Transcription Factor Skin Neoplasms DNA Copy Number Variations medicine.drug_class Primary Cell Culture Apoptosis Dermatology Biochemistry Polymorphism Single Nucleotide Romidepsin 03 medical and health sciences 0302 clinical medicine Depsipeptides medicine Tumor Cells Cultured Humans Sezary Syndrome Phosphorylation Molecular Biology Vorinostat Sezary Cell Skin Regulation of gene expression Chemistry Histone deacetylase inhibitor Cutaneous T-cell lymphoma Cell Biology HDACi STAT3 RAD23 Sezary Syndrome CTCL JAK primary T cells medicine.disease Neoplastic Cells Circulating DNA-Binding Proteins Gene Expression Regulation Neoplastic Histone Deacetylase Inhibitors 030104 developmental biology Trichostatin A DNA Repair Enzymes Drug Resistance Neoplasm 030220 oncology & carcinogenesis Gene Knockdown Techniques Cancer research Tyrosine Histone deacetylase medicine.drug |
| Zdroj: | Butler, R M, Mckenzie, R C, Jones, C L, Flanagan, C E, Woollard, W J, Demontis, M, Ferreira, S, Tosi, I, John, S, Whittaker, S J & Mitchell, T J 2019, ' Contribution of STAT3 and RAD23B in Primary Sézary Cells to Histone Deacetylase Inhibitor FK228 Resistance ', Journal of Investigative Dermatology, vol. 139, no. 9, pp. 1975-1984.e2 . https://doi.org/10.1016/j.jid.2019.03.1130 |
| Popis: | FK228 (romidepsin) and suberoylanilide hydroxamic acid (vorinostat) are histone deacetylase inhibitors (HDACi) approved by the US Food and Drug Administration for cutaneous T-cell lymphoma (CTCL), including the leukemic subtype Sezary syndrome. This study investigates RAD23B and STAT3 gene perturbations in a large cohort of primary Sezary cells and the effect of FK228 treatment on tyrosine phosphorylation of STAT3 (pYSTAT3) and RAD23B expression. We report RAD23B copy number variation in 10% (12/119, P ≤ 0.01) of SS patients, associated with reduced mRNA expression (P = 0.04). RAD23B knockdown in a CTCL cell line led to a reduction in FK228-induced apoptosis. Histone deacetylase inhibitor treatment significantly reduced pYSTAT3 in primary Sezary cells and was partially mediated by RAD23B. A distinct pattern of RAD23B-pYSTAT3 co-expression in primary Sezary cells was detected. Critically, Sezary cells harboring the common STAT3 Y640F variant were less sensitive to FK228-induced apoptosis and exogenous expression of STAT3 Y640F, and D661Y conferred partial resistance to STAT3 transcriptional inhibition by FK228 (P ≤ 0.0024). These findings suggest that RAD23B and STAT3 gene perturbations could reduce sensitivity to histone deacetylase inhibitors in SS patients. |
| Databáze: | OpenAIRE |
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