Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
Adv Sci (Weinh). 2024 Nov;11(44):e2402600. doi: 10.1002/advs.202402600. Epub 2024 Sep 28.
Temozolomide (TMZ) resistance is one of the major reasons for poor prognosis in patients with glioblastoma (GBM). Long noncoding RNAs (lncRNAs) are involved in multiple biological processes, including TMZ resistance. Linc00942 is a potential regulator of TMZ sensitivity in GBM cells is shown previously. However, the underlying mechanism of TMZ resistance induced by Linc00942 is unknown. In this study, the sequence of Linc00942 by rapid amplification of cDNA ends assay in TMZ-resistant GBM cells is identified and confirmed that Linc00942 contributes to self-renewal and TMZ resistance in GBM cells. Chromatin isolation by RNA purification followed by mass spectrometry (ChIRP-MS) and followed by Western blotting (ChIRP-WB) assays shows that Linc00492 interacted with TPI1 and PKM2, subsequently promoting their phosphorylation, dimerization, and nuclear translocation. The interaction of Linc00942 with TPI1 and PKM2 leads to increased acetylation of H3K4 and activation of the STAT3/P300 axis, resulting in the marked transcriptional activation of SOX9. Moreover, the knockdown of SOX9 reversed TMZ resistance induced by Linc00492 both in vitro and in vivo. In summary, Linc00942 strongly promotes SOX9 expression by interacting with TPI1 and PKM2 is found, thereby driving self-renewal and TMZ resistance in GBM cells. These findings suggest potential combined therapeutic strategies to overcome TMZ resistance in patients with GBM.
替莫唑胺（TMZ）耐药是胶质母细胞瘤（GBM）患者预后不良的主要原因之一。长链非编码 RNA（lncRNA）参与包括 TMZ 耐药在内的多种生物学过程。先前已经表明，Linc00942 是 GBM 细胞中 TMZ 敏感性的潜在调节因子。然而，Linc00942 诱导 TMZ 耐药的潜在机制尚不清楚。在这项研究中，通过快速扩增 cDNA 末端测定法在 TMZ 耐药性 GBM 细胞中鉴定出 Linc00942 的序列，并证实 Linc00942 有助于 GBM 细胞的自我更新和 TMZ 耐药性。RNA 纯化后染色质免疫沉淀测序（ChIRP-MS）和随后的 Western blot（ChIRP-WB）分析表明，Linc00942 与 TPI1 和 PKM2 相互作用，随后促进它们的磷酸化、二聚化和核易位。Linc00942 与 TPI1 和 PKM2 的相互作用导致 H3K4 的乙酰化增加和 STAT3/P300 轴的激活，从而导致 SOX9 的转录明显激活。此外，SOX9 的敲低在体外和体内均逆转了由 Linc00492 诱导的 TMZ 耐药性。总之，Linc00942 通过与 TPI1 和 PKM2 相互作用强烈促进 SOX9 的表达，从而驱动 GBM 细胞的自我更新和 TMZ 耐药性。这些发现表明，针对 Linc00942 的联合治疗策略可能克服 GBM 患者的 TMZ 耐药性。
