Epigenetic regulation of histone modifications in glioblastoma: recent advances and therapeutic insights

Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumor, characterized by its aggressive behavior, limited treatment options, and poor prognosis. Despite advances in surgery, radiotherapy, and chemotherapy, the median survival of GBM patients remains disappointingly short. Recent studies have underscored the critical role of histone modifications in GBM malignant progression and therapy resistance. Histones, protein components of chromatin, undergo various modifications, including acetylation and methylation. These modifications significantly affect gene expression, thereby promoting tumorigenesis and resistance to therapy. Targeting histone modifications has emerged as a promising therapeutic approach. Numerous pre-clinical studies have evaluated histone modification agents in GBM, including histone deacetylase inhibitors and histone methyltransferase inhibitors. These studies demonstrate that modulating histone modifications can alter gene expression patterns, inhibit tumor growth, induce apoptosis, and sensitize tumor cells to conventional treatments. Some agents have advanced to clinical trials, aiming to translate preclinical efficacy into clinical benefit. However, clinical outcomes remain suboptimal, as many agents fail to significantly improve GBM patient prognosis. These challenges are attributed to the complexity of histone modification networks and the adaptive responses of the tumor microenvironment. This review provides a comprehensive overview of epigenetic regulation mechanisms involving histone modifications in GBM, covering their roles in tumor development, tumor microenvironment remodeling, and therapeutic resistance. Additionally, the review discusses current clinical trials targeting histone modifications in GBM, highlighting successes, limitations, and future perspectives.

Keywords: Glioblastoma; Glioblastoma chemoresistance; Histone acetylation; Histone methylation; Histone modifications.

Fig. 1

Schematic overview of histone modifications and their regulatory roles in diverse biological processes in GBM. This schematic presents an overview of the main types of histone modifications identified in GBM and the key biological processes they regulate, including proliferation, cell cycle progression, apoptosis, migration, angiogenesis, metabolic reprogramming, therapeutic resistance, and the development of an immunosuppressive microenvironment. For abbreviations, see the abbreviations list

Fig. 2

Regulatory functions of histone acetylation–associated readers and writers in GBM. Histone acetylation readers (BET family) modulate GBM biological behaviors by interacting with multiple signaling pathways, such as PI3 K/AKT and MEK/ERK, and by influencing the tumor immune microenvironment (on the left side of the figure). Various HATs affect GBM cell proliferation, invasion, migration, apoptosis, and angiogenesis through different molecular pathways, including NF-κB and PI3 K/AKT (on the right side of the figure). For clarity, only major regulatory axes are depicted; further mechanistic details are discussed in the main text. For abbreviations, see the abbreviations list

Fig. 3

Roles of HDACs in modulating GBM biological behaviors. A HDACs regulate metabolic reprogramming in GBM, particularly pathways involved in the Warburg effect. B HDACs contribute to chemotherapy and radiotherapy resistance through mechanisms such as modulating MGMT expression and the DNA damage response. C HDACs impact GBM cell proliferation, invasion, migration, autophagy, and angiogenesis via multiple signaling pathways, including MEK/ERK, NF-κB, and PI3 K/AKT. For clarity, only representative pathways and functions are shown; detailed mechanisms are provided in the main text. For abbreviations, see the abbreviations list

Fig. 4

Regulatory roles of HDMs and HMTs in GBM. These enzymes modulate GBM cell behavior through various signaling pathways, such as AKT/mTOR and PTEN, affecting proliferation, invasion, cell survival, and other malignant traits. For clarity, only key mechanisms are illustrated; further details are available in the main text. For abbreviations, see the abbreviations list

Fig. 5

Rare histone modifications and their functions in GBM. Lactylation promotes GBM cell self-renewal, drug resistance, and proliferation via activation of pathways such as NF-κB and MAP4K4/JNK. Crotonylation, elevated by metabolic reprogramming in GSCs, coordinates with other histone modifications to regulate interferon signaling and CD8⁺ T cell infiltration, thereby facilitating tumor growth. Succinylation, catalyzed by KAT2A and α-KGDH, induces H3 K79 succinylation to support GBM cell proliferation and tumorigenesis. Only representative mechanisms are shown; further details are provided in the main text. For abbreviations, see the abbreviations list

Fig. 6

Combination therapy approaches targeting histone modifications in GBM. A Schematic of therapeutic strategies combining histone-modifying agents with radiotherapy, chemotherapy, targeted therapy, immunotherapy, and other epigenetic modulators to enhance GBM treatment efficacy. B Overview of representative pharmacological agents targeting histone acetylation and methylation in GBM. For abbreviations, see the abbreviations list