Lnc-TALC promotes O6-methylguanine-DNA methyltransferase expression via regulating the c-Met pathway by competitively binding with miR-20b-3p
Lnc-TALC promotes O6-methylguanine-DNA methyltransferase expression via regulating the c-Met pathway by competitively binding with miR-20b-3p
复制标题
Lnc-TALC 通过与 miR-20b-3p 竞争性结合调节 c-Met 途径促进 O6-甲基鸟嘌呤-DNA 甲基转移酶表达
DOI：
10.1038/s41467-019-10025-2
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发表时间：
2019-05-03
影响因子：
16.6
通讯作者：
Jiang, Chuanlu
中科院分区：
文献类型：
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作者：
Wu, Pengfei;Cai, Jinquan;Jiang, Chuanlu
长链非编码RNA（lncRNA）已成为新的调控分子，参与各种生物学过程，包括治疗耐药性。然而，胶质母细胞瘤（GBM）中lncRNA介导的替莫唑胺（TMZ）耐药性的机制在很大程度上仍然未知。为了说明lncRNA在TMZ抗性中的作用，我们诱导TMZ抗性GBM细胞，进行亲本和TMZ抗性细胞的lncRNA微阵列，并在GBM中发现未报道的lncRNA，lnc-TALC（胶质母细胞瘤复发中的替莫唑胺相关lncRNA），其通过竞争性结合miR-20 b-3 p以促进c-Met表达而与TMZ抗性相关。磷酸化AKT/FOXO 3轴调节TMZ抗性GBM细胞中的lnc-TALC表达。此外，lnc-TALC通过c-Met/Stat 3/p300轴介导MGMT启动子区H3 K9、H3 K27和H3 K36的乙酰化而增加MGMT表达。在临床患者中，lnc-TALC是TMZ耐药和GBM复发所必需的。我们的研究结果表明，GBM中的lnc-TALC可以作为克服TMZ耐药性的治疗靶点，增强TMZ化疗的临床益处。
Long noncoding RNAs (lncRNAs) have emerged as new regulatory molecules implicated in diverse biological processes, including therapeutic resistance. However, the mechanisms underlying lncRNA-mediated temozolomide (TMZ) resistance in glioblastoma (GBM) remain largely unknown. To illustrate the role of lncRNA in TMZ resistance, we induce TMZ-resistant GBM cells, perform a lncRNA microarray of the parental and TMZ-resistant cells, and find an unreported lncRNA in GBM, lnc-TALC (temozolomide-associated lncRNA in glioblastoma recurrence), correlated with TMZ resistance via competitively binding miR-20b-3p to facilitate c-Met expression. A phosphorylated AKT/FOXO3 axis regulated lnc-TALC expression in TMZ-resistant GBM cells. Furthermore, lnc-TALC increased MGMT expression by mediating the acetylation of H3K9, H3K27 and H3K36 in MGMT promoter regions through the c-Met/Stat3/p300 axis. In clinical patients, lnc-TALC is required for TMZ resistance and GBM recurrence. Our results reveal that lnc-TALC in GBM could serve as a therapeutic target to overcome TMZ resistance, enhancing the clinical benefits of TMZ chemotherapy.