Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen518107, China.
Department of Hematology, Zhongshan Hospital of Sun Yat-Sen University, Zhongshan528403, China.
Biol Chem. 2020 Mar 22;402(7):815-824. doi: 10.1515/hsz-2020-0345. Print 2021 Jun 25.
Emerging evidence shows that histone modification and its related regulators are involved in the progression and chemoresistance of multiple tumors including acute myeloid leukemia cells (AML). Our present study found that the expression of histone lysine demethylase Jumonji domain containing-3 (JMJD3) was increased in AML cells as compared with that in human primary bone marrow (HPBM) cells. Knockdown of JMJD3 can decrease the proliferation of AML cells and increase the chemosensitivity of daunorubicin (DNR) and cytarabine (Ara-C). By screening the expression of cytokines involved in AML progression, we found that knockdown of JMJD3 can inhibit the expression of interleukin-6 (IL-6). Recombinant IL-6 (rIL-6) can attenuate si-JMJD3-suppressed proliferation of AML cells. Mechanistically, JMJD3 can positively regulate the promoter activity and transcription of IL-6 mRNA, while had no effect on its mRNA stability. Further, JMJD3 can regulate the expression of p65, which can directly bind with promoter of IL-6 to increase its transcription. Over expression of p65 significantly attenuated si-JMJD3-suppressed expression of IL-6. Collectively, we revealed that JMJD3 can regulate the proliferation and chemosensitivity of AML cells via upregulation of IL-6. It suggested that JMJD3 might be a potential therapy target for AML treatment.
研究表明，组蛋白修饰及其相关调控因子参与了包括急性髓系白血病（AML）细胞在内的多种肿瘤的进展和耐药。本研究发现，与原代人骨髓细胞（HPBM）相比，组蛋白赖氨酸去甲基酶 JMJD3 在 AML 细胞中的表达增加。JMJD3 的敲低可降低 AML 细胞的增殖，并增加柔红霉素（DNR）和阿糖胞苷（Ara-C）的化疗敏感性。通过筛选参与 AML 进展的细胞因子表达，我们发现 JMJD3 的敲低可抑制白细胞介素 6（IL-6）的表达。重组白细胞介素 6（rIL-6）可减弱 si-JMJD3 对 AML 细胞增殖的抑制作用。机制上，JMJD3 可正向调节 IL-6 mRNA 的启动子活性和转录，而对其 mRNA 稳定性没有影响。此外，JMJD3 可以调节 p65 的表达，p65 可以直接与 IL-6 启动子结合，增加其转录。p65 的过表达显著减弱了 si-JMJD3 对 IL-6 表达的抑制作用。综上所述，我们揭示了 JMJD3 通过上调 IL-6 来调节 AML 细胞的增殖和化疗敏感性。这表明 JMJD3 可能是 AML 治疗的潜在治疗靶点。
