2. Academic Validation
  3. Delactylation of H3K9 by Sirtuin6 inhibits MGMT transcription and reverses temozolomide resistance in glioblastoma

Delactylation of H3K9 by Sirtuin6 inhibits MGMT transcription and reverses temozolomide resistance in glioblastoma

  • Int J Biol Macromol. 2025 Sep 2;327(Pt 1):147332. doi: 10.1016/j.ijbiomac.2025.147332.
Li Zou 1,  Zhimin Liu 2,  Luyao Peng 3,  Botao Wu 2,  Yongkai Huang 2,  Xianglan Wen 1,  Deqing Han 2,  Wenliang Tan 4,  Yang Zhou 5
Affiliations

Affiliations

  • 1 Department of Children Health Care Center, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou City, Hunan, China.
  • 2 Department of Neurosurgery, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou 412000, Hunan, China.
  • 3 Department of Anesthesiology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou City, Hunan, China.
  • 4 Department of Hepatobiliary and Pancreatic Surgery, Medical Center of Digestive Disease, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China. Electronic address: tanwenl@csu.edu.cn.
  • 5 Department of Neurosurgery, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou 412000, Hunan, China. Electronic address: zhouy_zzszxyy@163.com.
PMID: 40907925 DOI: 10.1016/j.ijbiomac.2025.147332
Abstract

Glioblastoma (GBM) stands as one of the most formidable and deadly brain cancers, with temozolomide (TMZ) established as the primary chemotherapeutic agent. However, over 50 % of patients showed innate or acquired resistance. Sirtuins, a family of NAD+-dependent deacetylases, have gained recognition as key regulators in shaping epigenetic landscapes and influencing chemoresistance across various cancers, yet their specific contribution to TMZ resistance in GBM has remained largely unexplored. In this study, we identified nuclear SIRT6 deficiency as a hallmark of TMZ-resistant GBM. Functionally, enhancing nuclear SIRT6 expression resensitized resistant cells to TMZ. Therapeutically, our findings demonstrated that combining the SIRT6 agonist MDL-800 with TMZ significantly inhibited cell proliferation and induced Apoptosis in TMZ-resistant GBM both in vitro and in vivo. Mechanistically, SIRT6 inhibited the transcription of MGMT by reducing histone H3K9 lactylation (H3K9la). Crucially, this process depends on the nuclear translocation of SIRT6, which enhances the therapeutic efficacy of TMZ. These findings establish the SIRT6-H3K9la-MGMT axis as a targetable vulnerability to overcome TMZ resistance in GBM treatment.

Keywords

Glioblastoma; Lactylation; MGMT; SIRT6; Temozolomide.

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