Department of Hematology and Hematology, Institute of Sun Yat-sen University, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Avenue, Guangzhou 510630, P. R. China.
Biol Chem. 2020 Dec 17;402(4):461-468. doi: 10.1515/hsz-2020-0196. Print 2021 Mar 26.
The chemoresistance is one of the major challenges for acute myeloid leukemia (AML) treatment. We found that the expression of histone deacetylase 8 (HDAC8) was increased in daunorubicin (DNR) resistant AML cells, while targeted inhibition of HDAC8 by its specific siRNA or inhibitor can restore sensitivity of DNR treatment . Further, targeted inhibition of HDAC8 can suppress expression of interleukin 6 (IL-6) and IL-8. While recombinant IL-6 (rIL-6) and rIL-8 can reverse si-HDAC8-resored DNR sensitivity of AML cells. Mechanistical study revealed that HDAC8 increased the expression of p65, one of key components of NF-κB complex, to promote the expression of IL-6 and IL-8. It might be due to that HDAC8 can directly bind with the promoter of p65 to increase its transcription and expression. Collectively, our data suggested that HDAC8 promotes DNR resistance of human AML cells via regulation of IL-6 and IL-8.
耐药性是急性髓系白血病（AML）治疗的主要挑战之一。我们发现组蛋白去乙酰化酶 8（HDAC8）在柔红霉素（DNR）耐药的 AML 细胞中表达增加，而通过其特异性 siRNA 或抑制剂靶向抑制 HDAC8 可以恢复 DNR 治疗的敏感性。此外，靶向抑制 HDAC8 可以抑制白细胞介素 6（IL-6）和 IL-8 的表达。而重组白细胞介素 6（rIL-6）和 rIL-8 可以逆转 si-HDAC8 恢复的 AML 细胞对 DNR 的敏感性。机制研究表明，HDAC8 通过增加 NF-κB 复合物关键组成部分之一 p65 的表达来增加 IL-6 和 IL-8 的表达。这可能是因为 HDAC8 可以直接与 p65 的启动子结合，增加其转录和表达。总之，我们的数据表明，HDAC8 通过调节 IL-6 和 IL-8 促进了人 AML 细胞对 DNR 的耐药性。
