Department of Respiratory and Critical Care Medicine, the 2nd Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun, 130041, P.R. China.
Department of Ultrasound, the 2nd Hospital of Jilin University, Changchun, 130041, P.R. China.
J Exp Clin Cancer Res. 2021 Feb 17;40(1):71. doi: 10.1186/s13046-021-01867-0.
Previous research has highlighted the ability of Homeobox A10 (HOXA10) to the promote proliferation, migration, and epithelial-mesenchymal transformation of various cancers, including lung adenocarcinoma (LAD), which is characterized by an aggressive disease course that exhibits rapid proliferation and migration, with studies suggesting histone deacetylase 1 (HDAC1) to be a downstream mediator of HOXA10. The current study aimed to investigate the mechanism by which HOXA10-mediated HDAC1 influences the development of LAD.
The expression patterns of HOXA10, HDAC1, DNA methyltransferase 1 (DNMT1), and Kruppel-like factor 4 (KLF4) were determined. Additionally, the effect of HOXA10, HDAC1, or DNMT1 on invasive phenotypes of LAD was analyzed using depletion experiments. The interactions among HOXA10, HDAC1, DNMT1, and KLF4 were evaluated via chromatin immunoprecipitation, dual luciferase assay or co-immunoprecipitation. Furthermore, the tumorigenic ability of the LAD cells following HOXA10 silencing and/or HDAC1 overexpression in vivo was also investigated.
In the LAD tissues and cells, HOXA10, HDAC1, and DNMT1 all exhibited high levels of expression, while KLF4 was poorly expressed. HOXA10 silencing inhibited the expression of HDAC1, reduced LAD cell proliferation, migration, and invasion, and promoted the apoptosis. HDAC1 promoted DNMT1 expression through deacetylation, and DNMT1 inhibited the KLF4 expression through DNA methyltransferase. The in vitro findings were further attested through the use of in vivo assays.
Taken together, the key observations of the current study highlight the role of HOXA10 and HDAC1 in promoting the proliferation and migration of LAD cells. HOXA10-induced upregulation of HDAC1 interacts with DNMT1-KLF4 axis, while the inhibition of HOXA10 or HDAC1 represents a promising anti-tumor therapy target for LAD.
先前的研究已经强调了同源盒 A10（HOXA10）促进各种癌症增殖、迁移和上皮-间充质转化的能力，包括肺腺癌（LAD），其具有侵袭性疾病过程，表现为快速增殖和迁移，研究表明组蛋白去乙酰化酶 1（HDAC1）是 HOXA10 的下游介质。本研究旨在探讨 HOXA10 介导的 HDAC1 影响 LAD 发生发展的机制。
确定 HOXA10、HDAC1、DNA 甲基转移酶 1（DNMT1）和 Kruppel 样因子 4（KLF4）的表达模式。此外，通过耗竭实验分析 HOXA10、HDAC1 或 DNMT1 对 LAD 侵袭表型的影响。通过染色质免疫沉淀、双荧光素酶测定或共免疫沉淀评估 HOXA10、HDAC1、DNMT1 和 KLF4 之间的相互作用。此外，还研究了 HOXA10 沉默和/或 HDAC1 过表达对体内 LAD 细胞致瘤能力的影响。
在 LAD 组织和细胞中，HOXA10、HDAC1 和 DNMT1 的表达水平均较高，而 KLF4 的表达水平较低。HOXA10 沉默抑制了 HDAC1 的表达，降低了 LAD 细胞的增殖、迁移和侵袭，并促进了细胞凋亡。HDAC1 通过去乙酰化促进 DNMT1 的表达，而 DNMT1 通过 DNA 甲基转移酶抑制 KLF4 的表达。体外研究结果通过体内研究得到进一步证实。
综上所述，本研究的主要发现强调了 HOXA10 和 HDAC1 在促进 LAD 细胞增殖和迁移中的作用。HOXA10 诱导的 HDAC1 上调与 DNMT1-KLF4 轴相互作用，而抑制 HOXA10 或 HDAC1 可能成为 LAD 的一种有前途的抗肿瘤治疗靶点。
