Department of Orthopedics, Second Affiliated Hospital & Institute of Cancer Stem Cell, Dalian Medical University, Dalian116027, China.
College of Stomatology, Dalian Medical University, Dalian 116044, China.
Neoplasia. 2017 Nov;19(11):908-918. doi: 10.1016/j.neo.2017.08.008. Epub 2017 Sep 21.
Chemoresistance remains a major drawback to osteosarcoma treatment. ZBTB7A, a member of the POK transcription repressor family, was shown to play an important role in tumorigenesis. However, the effect of ZBTB7A on osteosarcoma chemoresistance is completely unknown. In this study, we found that ZBTB7A is increased in cisplatin-resistant osteosarcoma cells and that elevated ZBTB7A inhibits cisplatin-induced apoptosis by repressing LINC00473 expression. Further mechanistic studies revealed that ZBTB7A directly binds to the promoter and suppresses the transcription of LINC00473. Additionally, our data indicate that LINC00473 interacts with the transcript factor C/EBPβ, facilitating its binding to the promoter of IL24, leading to decrease chemoresistance. Thus, these findings indicate that the ZBTB7A-mediated LINC00473-C/EBPβ-IL24 pathway is a promising novel target for overcoming cisplatin resistance in osteosarcoma.
化疗耐药仍然是骨肉瘤治疗的主要障碍。POK 转录阻遏家族的成员 ZBTB7A 被证明在肿瘤发生中发挥重要作用。然而，ZBTB7A 对骨肉瘤化疗耐药的影响尚完全不清楚。在本研究中，我们发现 ZBTB7A 在顺铂耐药骨肉瘤细胞中增加，并且升高的 ZBTB7A 通过抑制 LINC00473 的表达抑制顺铂诱导的细胞凋亡。进一步的机制研究表明，ZBTB7A 直接结合到启动子并抑制 LINC00473 的转录。此外，我们的数据表明 LINC00473 与转录因子 C/EBPβ 相互作用，促进其结合到 IL24 的启动子上，导致化疗耐药性降低。因此，这些发现表明 ZBTB7A 介导的 LINC00473-C/EBPβ-IL24 途径是克服骨肉瘤顺铂耐药性的有前途的新靶点。
