2. Academic Validation
  3. EPIC-0628 abrogates HOTAIR/EZH2 interaction and enhances the temozolomide efficacy via promoting ATF3 expression and inhibiting DNA damage repair in glioblastoma

EPIC-0628 abrogates HOTAIR/EZH2 interaction and enhances the temozolomide efficacy via promoting ATF3 expression and inhibiting DNA damage repair in glioblastoma

  • Cancer Lett. 2024 Apr 28:588:216812. doi: 10.1016/j.canlet.2024.216812.
Eryan Yang 1,  Biao Hong 2,  Yunfei Wang 2,  Qixue Wang 2,  Jixing Zhao 2,  Xiaoteng Cui 2,  Ye Wu 2,  Shixue Yang 2,  Dongyuan Su 2,  Xiaomin Liu 3,  Chunsheng Kang 4
Affiliations

Affiliations

  • 1 Lab of Neuro- Oncology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China; Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, 300052, China.
  • 2 Lab of Neuro- Oncology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
  • 3 Neuro-Oncology Center, Tianjin Huanhu Hospital, Nankai University, Tianjin, 300350, China.
  • 4 Lab of Neuro- Oncology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China. Electronic address: kang97061@tmu.edu.cn.
PMID: 38490327 DOI: 10.1016/j.canlet.2024.216812
Abstract

The efficacy of temozolomide (TMZ) treatment in glioblastoma (GBM) is influenced by various mechanisms, mainly including the level of O6-methylguanine-DNA methyltransferase (MGMT) and the activity of DNA damage repair (DDR) pathways. In our previous study, we had proved that long non-coding RNA HOTAIR regulated the GBM progression and mediated DDR by interacting with EZH2, the catalytic subunit of PRC2. In this study, we developed a small-molecule inhibitor called EPIC-0628 that selectively disrupted the HOTAIR-EZH2 interaction and promoted ATF3 expression. The upregulation of ATF3 inhibited the recruitment of p300, p-p65, p-Stat3 and SP1 to the MGMT promoter. Hence, EPIC-0628 silenced MGMT expression. Besides, EPIC-0628 induced cell cycle arrest by increasing the expression of CDKN1A and impaired DNA double-strand break repair via suppressing the ATF3-p38-E2F1 pathway. Lastly, EPIC-0628 enhanced TMZ efficacy in GBM in vitro and vivo. Hence, this study provided evidence for the combination of epigenetic drugs EPIC-0628 with TMZ for GBM treatment through the above mechanisms.

Keywords

Glioblastoma; HOTAIR; Homologous recombination; MGMT; Temozolomide.

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