WTAP promotes osteosarcoma tumorigenesis by repressing HMBOX1 expression in an m6A-dependent manner
WTAP promotes osteosarcoma tumorigenesis by repressing HMBOX1 expression in an m6A-dependent manner
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WTAP 通过 m(6)A 依赖性抑制 HMBOX1 表达促进骨肉瘤肿瘤发生
DOI：
10.1038/s41419-020-02847-6
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发表时间：
2020-08-19
影响因子：
9
通讯作者：
Li, Jinsong
中科院分区：
文献类型：
--
作者：
Chen, Shijie;Li, Yuezhan;Li, Jinsong
N-6-甲基腺苷 (m(6)A) 调节剂通过调节 m(6)A 修饰参与各种癌症的进展。然而，m(6)A 修饰在骨肉瘤中的潜在作用和机制仍不清楚。本研究发现WTAP在骨肉瘤组织中高表达，是骨肉瘤总体生存的独立预后因素。从功能上来说，WTAP作为癌基因，参与骨肉瘤体内外的增殖和转移。从机制上讲，M(6)A 斑点印迹、RNA-seq 和 MeRIP-seq、MeRIP-qRT-PCR 和荧光素酶报告基因检测表明 HMBOX1 被确定为 WTAP 的靶基因，WTAP 通过 HMBOX1 mRNA 3' UTR 处的 m(6)A 修饰调节 HMBOX1 稳定性。此外，HMBOX1表达在骨肉瘤中下调，是骨肉瘤患者总生存的独立预后因素。沉默的 HMBOX1 明显减弱了 shWTAP 介导的体内和体外对骨肉瘤生长和转移的抑制作用。最后，WTAP/HMBOX1通过PI3K/AKT途径调节骨肉瘤的生长和转移。总之，本研究证明了 WTAP 介导的 m(6)A 修饰在骨肉瘤进展中的关键作用，这可以为骨肉瘤治疗提供新的见解。
N-6-methyladenosine (m(6)A) regulators are involved in the progression of various cancers via regulating m(6)A modification. However, the potential role and mechanism of the m(6)A modification in osteosarcoma remains obscure. In this study, WTAP was found to be highly expressed in osteosarcoma tissue and it was an independent prognostic factor for overall survival in osteosarcoma. Functionally, WTAP, as an oncogene, was involved in the proliferation and metastasis of osteosarcoma in vitro and vivo. Mechanistically, M(6)A dot blot, RNA-seq and MeRIP-seq, MeRIP-qRT-PCR and luciferase reporter assays showed that HMBOX1 was identified as the target gene of WTAP, which regulated HMBOX1 stability depending on m(6)A modification at the 3 ' UTR of HMBOX1 mRNA. In addition, HMBOX1 expression was downregulated in osteosarcoma and was an independent prognostic factor for overall survival in osteosarcoma patients. Silenced HMBOX1 evidently attenuated shWTAP-mediated suppression on osteosarcoma growth and metastasis in vivo and vitro. Finally, WTAP/HMBOX1 regulated osteosarcoma growth and metastasis via PI3K/AKT pathway. In conclusion, this study demonstrated the critical role of the WTAP-mediated m(6)A modification in the progression of osteosarcoma, which could provide novel insights into osteosarcoma treatment.