HDAC7 drives glioblastoma to a mesenchymal-like state via LGALS3-mediated crosstalk between cancer cells and macrophages.

in Theranostics by Shulin Zhao, Rongrong Zhao, Chuanzheng Wang, Caizhi Ma, Zijie Gao, Boyan Li, Yanhua Qi, Wei Qiu, Ziwen Pan, Shaobo Wang, Qindong Guo, Jiawei Qiu, Yang Fan, Xiaofan Guo, Hao Xue, Lin Deng, Gang Li

TLDR

  • This study identified a novel HDAC7-H3K27ac-SOX8/JUN-LGALS3-ITGB1 axis that maintains the crosstalk between mesenchymal GBM and M2 macrophages. Blocking LGALS3 improved the therapeutic sensitivity of HDAC inhibitors, highlighting the potential therapeutic benefit of targeting HDAC7 and LGALS3 in GBM.
  • Key Insights: - HDAC7 inhibition reduced SOX8 expression and LGALS3 secretion - LGALS3 binding to ITGB1 facilitated the transition of mesenchymal GBM and M2 polarization of MDMs - Blocking LGALS3 improved the therapeutic sensitivity of HDAC inhibitors

Abstract

Glioblastoma multiforme (GBM) is an aggressive brain tumour for which current traditional treatment approaches have been unsuccessful, owing to the high genetic heterogeneity and immunosuppressive tumour microenvironment.Single-cell and spatial transcriptomic data revealed the niche-specific enrichment of mesenchymal-like (MES-like) GBM cells and monocyte-derived macrophages (MDMs); Gain- and loss-of-function assays of HDAC7 was confirmed bothandassays. Mechanistically, mass spectrum, RNA immunoprecipitation (RIP), and co-immunoprecipitation assays were conducted.We found that HDAC7, which upregulated by TRIM28-mediated sumoylation at the protein levels, inhibited SOX8 expression by mediating H3K27 deacetylation. And the down-regulated SOX8 facilitated the transcriptional activity of JUN, to induce LGALS3 secretion, which then bind to the membrane protein ITGB1 on GSC and MDMs in the autocrine and paracrine manners to facilitate the transformation of the mesenchymal phenotype of GBM and the M2 polarization of MDMs, respectively. In turn, LGALS3 could also secreted by M2 MDMs to promote MES transition of GBM in a paracrine manner, creating a positive feedback loop. In translational medicine, we found that blocking LGALS3 improved the therapeutic sensitivity of HDAC inhibitors.Our findings revealed the role of the novel HDAC7-H3K27ac-SOX8/JUN-LGALS3-ITGB1 axis in maintaining the crosstalk between MES GBM and M2 MDM, highlighting that HDAC7 and LGALS3 may serve as potential prognostic biomarkers and therapeutic targets in GBM.

Overview

  • The study aimed to investigate the role of HDAC7 in glioblastoma multiforme (GBM) and its potential as a therapeutic target.
  • The researchers used single-cell and spatial transcriptomic data to identify the niche-specific enrichment of mesenchymal-like GBM cells and monocyte-derived macrophages.
  • The study found that HDAC7 plays a crucial role in maintaining the crosstalk between mesenchymal GBM and M2 macrophages, highlighting its potential as a prognostic biomarker and therapeutic target.

Comparative Analysis & Findings

  • The study found that HDAC7 inhibition reduced the expression of SOX8, which in turn reduced the transcriptional activity of JUN and reduced the secretion of LGALS3.
  • The researchers demonstrated that LGALS3 binding to ITGB1 on GBM stem cells and MDMs facilitated the transformation of the mesenchymal phenotype of GBM and M2 polarization of MDMs, respectively.
  • Blocking LGALS3 improved the therapeutic sensitivity of HDAC inhibitors, highlighting the potential therapeutic benefit of targeting HDAC7 and LGALS3 in GBM.

Implications and Future Directions

  • The study's findings highlight the potential of HDAC7 and LGALS3 as biomarkers and therapeutic targets in GBM, providing new avenues for the development of targeted therapies.
  • Future studies should investigate the specific mechanisms by which HDAC7 regulates SOX8 and JUN, as well as the optimal dosage and duration of therapy for targeting HDAC7 and LGALS3.
  • The study's findings also underscore the importance of considering the tumour microenvironment in the development of effective therapeutic strategies for GBM.
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