LncRNA-Mediated TPI1 and PKM2 Promote Self-Renewal and Chemoresistance in GBM.

in Advanced science (Weinheim, Baden-Wurttemberg, Germany) by Changxiao Yang, Ziwei Li, Kaifu Tian, Xiangqi Meng, Xinyu Wang, Dan Song, Xuan Wang, Tianye Xu, Penggang Sun, Junzhe Zhong, Yu Song, Wenbin Ma, Yuxiang Liu, Daohan Yu, Ruofei Shen, Chuanlu Jiang, Jinquan Cai

TLDR

  • The study investigates how a type of RNA called Linc00942 affects the sensitivity of brain tumor cells to a drug called Temozolomide. The authors found that Linc00942 is more highly expressed in brain tumor cells that are resistant to Temozolomide. They also found that Linc00942 promotes the growth and survival of these brain tumor cells. The study shows that Linc00942 interacts with two other proteins called TPI1 and PKM2, which leads to increased activity in the brain and promotes the growth of brain tumor cells. The study also shows that the knockdown of a protein called SOX9 can reverse the effects of Linc00942 on brain tumor cells. The study's findings suggest that Linc00942 could be a potential target for new treatments for brain tumors.

Abstract

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.

Overview

  • The study investigates the role of Linc00942 in TMZ resistance in GBM cells. The authors identify the sequence of Linc00942 in TMZ-resistant GBM cells and confirm its contribution to self-renewal and TMZ resistance. They use ChIRP-MS and ChIRP-WB assays to show that Linc00942 interacts with TPI1 and PKM2, leading to increased acetylation of H3K4 and activation of the STAT3/P300 axis. The knockdown of SOX9 reverses TMZ resistance induced by Linc00942 both in vitro and in vivo. The study aims to understand the underlying mechanism of TMZ resistance induced by Linc00942 and identify potential therapeutic strategies to overcome it in GBM patients.

Comparative Analysis & Findings

  • The study compares the outcomes observed in TMZ-resistant and TMZ-sensitive GBM cells. The authors found that Linc00942 is more highly expressed in TMZ-resistant GBM cells than in TMZ-sensitive cells. They also found that Linc00942 promotes self-renewal and TMZ resistance in GBM cells. The study identifies that Linc00942 interacts with TPI1 and PKM2, leading to increased acetylation of H3K4 and activation of the STAT3/P300 axis. The knockdown of SOX9 reverses TMZ resistance induced by Linc00942 both in vitro and in vivo. The key findings of the study suggest that Linc00942 promotes SOX9 expression by interacting with TPI1 and PKM2, thereby driving self-renewal and TMZ resistance in GBM cells.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The identification of Linc00942 as a potential regulator of TMZ sensitivity in GBM cells could lead to the development of new therapeutic strategies to overcome TMZ resistance in patients with GBM. The study's findings also suggest that the interaction of Linc00942 with TPI1 and PKM2 leads to increased acetylation of H3K4 and activation of the STAT3/P300 axis, which could be targeted for therapeutic purposes. The study's limitations include the use of in vitro and in vivo models, which may not fully capture the complexity of TMZ resistance in GBM patients. Future research could explore the role of Linc00942 in other types of cancer and investigate its potential as a therapeutic target in combination with other drugs. The study's findings also suggest that the knockdown of SOX9 could be a potential therapeutic strategy to overcome TMZ resistance in GBM patients. Future research could investigate the safety and efficacy of SOX9 knockdown in clinical trials.
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