Histone PTMs and Cancer: Beyond Classical Oncogenes

Histone posttranslational modifications (PTMs) represent a fundamental epigenetic mechanism governing chromatin structure and gene expression. Critically, these modifications can promote tumorigenesis independently of classical oncogenes like RAS or p53.

Recent research reveals that dysregulated histone PTM reprogramming contributes significantly to oncogenesis. This dysregulation fosters genomic instability, enables immune evasion, and disrupts metabolic homeostasis. Consequently, aberrant histone PTMs have emerged as promising novel targets for anticancer therapeutics.

This review examines the non-classical oncogenic mechanisms mediated by histone PTMs and evaluates their potential for clinical translation.

Biological Basis of Histone PTMs

Histone posttranslational modifications (PTMs) encompass diverse chemical alterations, including methylation, acetylation, and phosphorylation. These modifications occur at over 60 distinct amino acid residues, predominantly within the tails of histones H3 and H4.

Collectively, these PTMs form a regulatory "histone code." Their establishment, removal, and interpretation are governed by three specialized functional classes:

• Writers: Enzymes catalyzing modifications (e.g., histone methyltransferase EZH2, acetyltransferase p300).
• Erasers: Enzymes removing modifications (e.g., histone demethylase LSD1, deacetylases HDACs).
• Readers: Domains/proteins recognizing specific marks (e.g., bromodomain Brd4 binding acetylated lysines).

Mechanistically, histone PTMs influence cancer development by modulating chromatin architecture and gene expression. They achieve this either by altering the histone's electrostatic charge or by recruiting effector protein complexes. Consequently, PTMs directly regulate chromatin compaction states—for instance, H3K9me3 modification promotes heterochromatin formation—thereby controlling the transcriptional activity of oncogenes and tumor suppressor genes.

Abnormal Patterns and Functions of PTMs in Cancer

1. Dysregulation of Classical Modifications Drives Malignant Transformation

Specific histone posttranslational modifications (PTMs) exhibit distinct tumor-suppressive or oncogenic roles, contributing to cancer pathogenesis:

• Mechanistic Consequences of Key Alterations:
  • H3K27me3 Loss: Drives chromatin hyperaccessibility, resulting in oncogene overexpression (e.g., Myc). Concurrently, Polycomb complexes abnormally silence tumor suppressor genes (e.g., CDKN2A). This dual dysregulation promotes uncontrolled proliferation and is prevalent in >70% of glioblastoma multiforme cases.
  • H4K20me3 Loss: Compromises heterochromatin integrity, inducing genomic instability. This defect synergizes with TP53 mutations in breast cancer pathogenesis.
  • Elevated H3K9ac/H3K14ac: Promotes chromatin relaxation, activating pro-metastatic pathways like Wnt/β-catenin. This mechanism underlies key drug resistance phenotypes in ovarian cancer.
  • H3K79me2 Dysregulation: Sustains MLL fusion protein activity, critically enabling leukemic stem cell self-renewal (Noberini R et al., 2018).
• In breast cancer, the dysregulation of histone modifications—including the reduced expression of markers such as H3K9ac, H3K18ac, and H4K12ac—is strongly correlated with the development of aggressive tumor subtypes and clinical outcomes.
  • Association with Molecular Subtypes: Distinct epigenetic patterns are observed across different breast cancer subtypes. The Luminal subtype, which typically carries a more favorable prognosis, often maintains high levels of specific histone acetylation and methylation, such as elevated H3K18ac. Conversely, the basal-like subtype—known for its aggressive behavior—frequently demonstrates a significant loss of these same modifications. This stark contrast indicates that epigenetic reprogramming is a key driver of tumor heterogeneity.
  • Value in Early Diagnosis: Certain histone modification changes can serve as early indicators of disease progression. For instance, the loss of H4K16ac and a state of H4K12ac hypoacetylation are promising biomarkers for detecting the critical transition from ductal carcinoma in situ to invasive carcinoma.
  • Implications for Prognostic Stratification: The hypoacetylation or low expression of pivotal histone marks, including H4R3me2, is directly linked to poorer overall survival rates. This relationship offers a potential new avenue for prognostic stratification and a target for precision therapies that operate independently of traditional receptor status (McAnena P et al., 2017).

Posttranslational modifications to Histone 3 and 4 found in breast cancer (McAnena P et al., 2017)

2. Expanding the Dimensions of Cancer Regulation Through Novel PTMs

Recent research has established a direct connection between tumor metabolism and epigenetic regulation through newly discovered post-translational modifications (PTMs), such as lactylation and crotonylation.

• Histone Lactylation (H3K18la) in PDAC: Dysregulated histone lactylation, particularly elevated H3K18la, promotes tumor progression in pancreatic ductal adenocarcinoma (PDAC) via a metabolic-epigenetic feedback loop.
  • Pathogenic Mechanism: A hypermetabolic state induces lactate accumulation, which activates the acetyltransferase P300 to deposit H3K18la modifications. This epigenetic mark subsequently enhances the transcription of key mitotic checkpoint genes, including TTK and BUB1B.
  • The Vicious Cycle: The resulting TTK protein phosphorylates and activates lactate dehydrogenase A (LDHA), catalyzing further lactate production. This amplifies H3K18la modification, creating a self-reinforcing "Glycolysis–H3K18la–TTK/BUB1B" circuit that drives malignancy.
  • Clinical Relevance: High H3K18la levels are a biomarker of poor patient prognosis. Importantly, inhibiting either LDHA or glycolysis disrupts this oncogenic loop and suppresses tumor growth (Li F et al., 2024).

A positive feedback loop between H3K18la target genes (TTK and BUB1B) and glycolysis (Li F et al., 2024)

• Succinylation (H3K79succ): In Hepatitis B virus (HBV) infection, dysregulated histone succinylation, specifically at H3K79, directly facilitates viral replication through epigenetic mechanisms.
  • Pathogenic Mechanism: The viral covalently closed circular DNA (cccDNA) recruits the succinyltransferase GCN5. This enzyme catalyzes H3K79 succinylation, remodeling the local chromatin into a transcriptionally active state. This permissive environment enhances viral gene expression, leading to increased levels of HBV DNA, HBsAg, and HBeAg.
  • Therapeutic Target: Interferon-α (IFN-α) presents a potent therapeutic strategy by targeting this pathway. It significantly suppresses viral load through a dual mechanism: inhibiting GCN5-mediated H3K79 succinylation and directly destabilizing the cccDNA reservoir (Yuan Y et al., 2020).

IFN-α depresses the succinylation of histone H3K79 on HBV cccDNA minichromosome (Yuan Y et al., 2020)

PTMs as Novel Targets for Cancer Diagnosis and Treatment

1. Diagnostic Biomarkers

Circulating nucleosomes carry stable histone post-translational modifications (PTMs), which have emerged as powerful diagnostic tools surpassing conventional tumor markers. These biomarkers include classical histone marks (e.g., H3K9me3, H4K20me3, H3K27me3) and novel epigenetic regulators (e.g., H2A.Z, H2AK119ub).

• Early Colorectal Cancer Screening: A combined detection panel of H3K27me3 and H4K20me3 demonstrates high specificity (90%).
• Pancreatic Cancer Diagnosis: An epigenetic signature comprising 5mC, H2A.Z, H2A.A, H3K4me2, and H2AK119ub shows potential to replace the traditional CA19-9 biomarker.
• Prognosis Monitoring: Elevated H3K27me3 levels correlate with reduced survival in breast and ovarian cancers, while loss of H4K20me3 predicts higher metastatic risk in colorectal cancer.
• Pan-Cancer PTM Atlas: Global profiling of phosphorylation and acetylation patterns can classify immune microenvironment subtypes. For instance, "cold" tumors often exhibit elevated acetylation of metabolic proteins (McAnena P et al., 2017).

2. Targeted Therapeutic Strategies

Therapeutic efforts are focused on developing agents to modulate these aberrant PTM pathways.

Understanding histone ptms in neurobiology can be consulted "Histone PTMs in Neurobiology: From Memory to Neurodegeneration".

For more research on histone PTM biomarkers see "Histone PTMs as Biomarkers: Opportunities and Limitations for Translational Research".

Challenges and Future Directions

Model Limitations

Conventional in vitro cell culture systems induce widespread, artificial reprogramming of the PTM landscape, such as the loss of repressive H3K27me3 marks. To achieve greater physiological relevance, future research must prioritize models that more accurately recapitulate the in vivo state, such as patient-derived organoids and xenografts (PDX).

Technological Innovation

Single-Molecule PTM Imaging: Emerging technologies capable of tracking the real-time dynamics of histone modifications in live cells.

Artificial Intelligence: Leveraging AI and machine learning to predict complex relationships between PTM patterns and disease phenotypes, thereby accelerating the design and optimization of targeted therapeutics.

Clinical Translation

Bridging these discoveries to the clinic requires two key advances: first, the development of tissue-specific drug delivery systems to enhance on-target efficacy; and second, a deeper investigation into the synergistic potential of combining PTM-targeting agents with established immunotherapies, such as PD-1/PD-L1 inhibitors.

Conclusion

Histone PTMs constitute a powerful layer of epigenetic control that drives tumor malignancy independent of genetic mutations. The specific patterns of these aberrant modifications provide a robust new framework for molecular classification and unveil a promising array of therapeutic targets. Future progress in precision medicine will depend on integrating advanced tools—including nano-delivery platforms, single-cell multi-omics, and dynamic modification monitoring—to realize the full potential of epigenetic therapy and move beyond a purely gene-centric view of cancer.

Core Idea: Cancer is not solely a genetic disease but also a disorder of the epigenome. Targeting pathogenic PTM networks opens a crucial "second front" in the war against cancer.

References

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2. McAnena P, Brown JA, Kerin MJ. Circulating Nucleosomes and Nucleosome Modifications as Biomarkers in Cancer. Cancers (Basel). 2017 Jan 8;9(1):5. doi: 10.3390/cancers9010005. PMID: 28075351; PMCID: PMC5295776.
3. Li F, Si W, Xia L, Yin D, Wei T, Tao M, Cui X, Yang J, Hong T, Wei R. Positive feedback regulation between glycolysis and histone lactylation drives oncogenesis in pancreatic ductal adenocarcinoma. Mol Cancer. 2024 May 6;23(1):90. doi: 10.1186/s12943-024-02008-9. PMID: 38711083; PMCID: PMC11071201.
4. Yuan Y, Yuan H, Yang G, Yun H, Zhao M, Liu Z, Zhao L, Geng Y, Liu L, Wang J, Zhang H, Wang Y, Zhang XD. IFN-α confers epigenetic regulation of HBV cccDNA minichromosome by modulating GCN5-mediated succinylation of histone H3K79 to clear HBV cccDNA. Clin Epigenetics. 2020 Sep 7;12(1):135.