Pediatric Intensive Care Units, Shangqiu first People's Hospital, Shangqiu, 476100, China.
Pediatric Intensive Care Units, Shangqiu first People's Hospital, Shangqiu, 476100, China.
Biomed Pharmacother. 2019 Jan;109:1793-1801. doi: 10.1016/j.biopha.2018.11.003. Epub 2018 Nov 26.
Increasing evidence has suggested the involvement of long non-coding RNA (lncRNA) taurine upregulated gene 1 (TUG1) in chemoresistance of cancer treatment. However, its function and molecular mechanisms in acute myeloid leukemia (AML) chemoresistance are still not well elucidated. In the present study, we investigate the functional role of TUG1 in Adriamycin (ADR) resistance of AML and discover the underlying molecular mechanism. Our study revealed that TUG1 was up-regulated in ADR-resistant AML tissues and cells. High TUG1 expression was correlated with poor prognosis of AML patients. TUG1 knockdown improved the sensitivity of HL60/ADR cells to ADR. Moreover, TUG1 could epigenetically suppress miR-34a expression via recruiting Enhancer of zeste homolog 2 (EZH2). miR-34a overexpression could mimic the functional role of down-regulated TUG1 in ADR resistance. miR-34a knockdown counteracted the inductive effect of TUG1 inhibition on ADR sensitivity of HL60/ADR cells. Furthermore, TUG1 knockdown facilitated ADR sensitivity of ADR-resistant AML cells in vivo. In summary, TUG1 knockdown overcame ADR resistance of AML by epigenetically enhancing miR-34a expression, providing a novel therapeutic target for AML.
越来越多的证据表明，长非编码 RNA（lncRNA）牛磺酸上调基因 1（TUG1）参与了癌症治疗的化疗耐药性。然而，其在急性髓系白血病（AML）化疗耐药性中的功能和分子机制仍未得到充分阐明。在本研究中，我们研究了 TUG1 在阿霉素（ADR）耐药性 AML 中的功能作用，并发现了潜在的分子机制。我们的研究表明，TUG1 在 ADR 耐药性 AML 组织和细胞中上调。高 TUG1 表达与 AML 患者的预后不良相关。TUG1 敲低可提高 HL60/ADR 细胞对 ADR 的敏感性。此外，TUG1 可以通过招募 Enhancer of zeste homolog 2（EZH2）来表观遗传抑制 miR-34a 的表达。miR-34a 的过表达可以模拟下调 TUG1 在 ADR 耐药性中的功能作用。miR-34a 的敲低可抵消 TUG1 抑制对 HL60/ADR 细胞 ADR 敏感性的诱导作用。此外，TUG1 敲低可促进体内 ADR 耐药性 AML 细胞对 ADR 的敏感性。总之，TUG1 敲低通过表观遗传增强 miR-34a 的表达克服了 AML 的 ADR 耐药性，为 AML 提供了一个新的治疗靶点。
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