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Tsoneva, D.K.;  Ivanov, M.N.;  Conev, N.V.;  Manev, R.;  Stoyanov, D.S.;  Vinciguerra, M. Circulating Histones to Detect and Monitor Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/40484 (accessed on 24 December 2025).
Tsoneva DK,  Ivanov MN,  Conev NV,  Manev R,  Stoyanov DS,  Vinciguerra M. Circulating Histones to Detect and Monitor Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/40484. Accessed December 24, 2025.
Tsoneva, Desislava K., Martin N. Ivanov, Nikolay Vladimirov Conev, Rostislav Manev, Dragomir Svetozarov Stoyanov, Manlio Vinciguerra. "Circulating Histones to Detect and Monitor Cancer" Encyclopedia, https://encyclopedia.pub/entry/40484 (accessed December 24, 2025).
Tsoneva, D.K.,  Ivanov, M.N.,  Conev, N.V.,  Manev, R.,  Stoyanov, D.S., & Vinciguerra, M. (2023, January 23). Circulating Histones to Detect and Monitor Cancer. In Encyclopedia. https://encyclopedia.pub/entry/40484
Tsoneva, Desislava K., et al. "Circulating Histones to Detect and Monitor Cancer." Encyclopedia. Web. 23 January, 2023.
Circulating Histones to Detect and Monitor Cancer
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This entry is adapted from the peer-reviewed paper 10.3390/ijms24020942

Liquid biopsies have emerged as a minimally invasive cancer detection and monitoring method, which could identify cancer-related alterations in nucleosome or histone levels and modifications in blood, saliva, and urine. Histones, the core component of the nucleosome, are essential for chromatin compaction and gene expression modulation. Increasing evidence suggests that circulating histones and histone complexes, originating from cell death or immune cell activation, could act as promising biomarkers for cancer detection and management.

liquid biopsy histones cancer cell-free DNA nucleosome

1. Circulating histones

In eukaryotic cells, DNA is compacted into chromatin by wrapping around histone complexes called nucleosomes [1]. The nucleosome is composed of approximately 147 base pairs of DNA coiled around two H2A-H2B dimers and one H3-H4 tetramer [2][3]. Adjacent nucleosomes are connected through a “linker DNA” of approximately 20–80 base pairs in length, bound by histone H1 [1][2]. The nucleosomes are the core of chromatin and are essential for consistent and accurate DNA replication, transcription, and repair. It is clear that the correct orchestration of nucleosome regulation is vital for genome integrity.
The numerous protein-protein and protein-DNA interactions make the nucleosome highly stable [2][3], yet not static [4]. The histones contain so-called N-terminal histone tails, which protrude out of the octamer and are subjected to post-translational marks (PTMs), which alter the conformation and the interaction properties of the nucleosome. Furthermore, nucleosomes consist of distinct histone variants, resulting in structural variations linked to distinct functions. The nucleosome positioning is also very dynamic. As the level of chromatin compaction lies at the center of gene expression regulation, the nucleosomes should be able to alternate their place and state. To do so, the nucleosomal histones interact with various proteins in a highly organized spatiotemporal manner. Furthermore, to maintain genomic stability, nucleosomes are continuously undergoing assembly and disassembly [5]. Both processes are directly linked to histone synthesis and degradation [5]. Histone proteins have a long half-life of approximately 220 days [6][7][8]. Nevertheless, it should be taken into account that histones in different cells/tissues and chromatin regions exhibit significant differences in their half-lives [9]. For instance, the histone turnover in hepatocytes was shown to occur relatively fast (18–61 h) compared to the brain (~72 days) [8]; however, this was notably slower in comparison to fast turnover proteins (~9–11 h).
Circulating histones and nucleosomes can be detected in healthy and diseased conditions among individuals. While the main source of circulating histones is believed to be apoptotic and necrotic cells [10], histones can be secreted into the extracellular space by activated cells, acting as damage-associated molecular pattern molecules [11][12][13][14]. Neutrophils can exert a specific immune defense mechanism, referred to as “neutrophil extracellular traps” (NETs) [15], in which genomic DNA, core histones, and antimicrobial factors are released by neutrophils to degrade invading pathogens [15][16]. Of note, such extracellular traps have also been reported in subsequent studies for macrophages, mast cells, and eosinophils [17][18][19][20][21][22], further supporting the role of histones in the immune response [11][12][13]. NETs can subsequently cause a specific form of cell death (“NETosis”), leading to further histone release [23]. Furthermore, histones released in the extracellular space in response to apoptotic signals can trigger an apoptotic cascade [24]. For example, hyperacetylated H3.3 accumulates in the extracellular space due to resistance to proteasomal degradation and facilitates apoptosis in lung cells, resulting in H3.3-mediated lung injury [24]. Administration of histone antibodies resulted in reversed cytotoxicity [24][25][26], directly linking histone release as a driver of toxicity.
Together, previous findings highlight the potential significance of circulating histones in the modulation of inflammation, which is tightly linked to cancer pathogenesis [27].

2. Tracing the Tissue of Origin of Circulating Histones

A crucial limitation of circulating histones and histone complexes as biomarkers for cancer detection and monitoring is the identification of the detected histones tissue-of-origin, which is of utmost importance for early detection and diagnostics of cancer, and disease progression monitoring. The main challenges lie in establishing the composition of circulating histone complexes and the prerequisite for genetic differences between healthy and tumor samples, which is further exacerbated as tumors often present no or unknown genetic mutations within the histones. A notable exception may be diffuse midline glioma (DMG), a highly morbid pediatric brain tumor: up to 80% of DMGs harbor mutations in histone H3-encoding genes, which is associated with poor prognosis [28][29]. Among these, recurrent and somatic H3.3K27M mutations can be detected using qPCR at the ctDNA level in DMG cerebrospinal fluid (CSF), plasma, and primary tumor specimens, using a standardized protocol that does not involve assessing the protein levels [29]. Moreover, as previously mentioned, H3Cit, which is involved in NETs formation [30], can be promptly measured by enzyme-linked immunosorbent assay (ELISA) in biological fluids and correlates with the diagnosis and prognosis of several tumor types [31][32][33]. However, H3Cit is released from neutrophils and it is not tumor-specific.
Cell-free DNA (cfDNA) generally refers to DNA bound to histone complexes [34][35], as naked DNA in circulation is rapidly digested by nucleases [36][37][38]. Furthermore, previous analysis of circulating DNA fragments showed peaks corresponding to approximately 147bp [39]. Snyder et al. suggested that the fragmentation pattern of circulating DNA could reveal information on the epigenetic signature of the fragment-releasing cell [40]. Given that cells and tissues in healthy and diseased conditions are characterized by specific epigenetic profiles [41][42][43][44], sequencing and mapping of cfDNA fragments, and thus, nucleosome occupancy could identify the tissue-of-origin of the cfDNA. The authors showed that the cfDNA fragmentation pattern is indicative of nucleosome positioning at the transcriptional start site and gene bodies and correlates with gene expression signature, cell lineages, and tissue types [40]. Importantly, nucleosome spacing in cfDNA, isolated from patients with diverse solid cancer types, was able to identify various non-hematopoietic contributors. Of note, in some cases, the top-ranked cell lines and tissues analyzed were aligned with the identified patient’s cancer type, indicating a potential value of the approach in cancer diagnostics. In comparison, the top-ranked correlations in healthy individuals were lymphoid and myeloid lineages [40], which is in line with hematopoietic cell turnover as the prime cfDNA source [45]. These findings suggest that the measurement of circulating histones and histone complexes, together with the establishment of the nucleosome footprint by sequencing the associated DNA, could be applied to establish an elaborate cancer (location) detection and monitoring approach.
Nevertheless, Snyder et al. showed that in some instances, the highest-ranked cell lines were aligned poorly with the cell types, which could be associated with an underrepresentation of the specific cancer types in the used datasets [40]. Therefore, the potential application of nucleosome footprinting in cancer care could depend on advancements in tumor heterogeneity characterization and the generation of detailed referenced datasets. Furthermore, relatively low coverage of transcriptional start sites was achieved [40], which could render the approach less powerful. While, currently, ex vivo nucleosome footprinting seems unlikely to outperform the sensitivity and specificity of the currently applied diagnostic methods, it might prove valuable in characterizing cancers with an unknown primary origin, supplementing diagnostics and invasive biopsies-mediated cancer subtyping.

3. Circulating Histones in Hematological Malignancies: Markers, Predictors, and Therapeutic Potential

Hematologic malignancies originate from blood cells or blood-forming tissue and are subdivided depending on the type of the affected cell. Leukemia is a hematologic malignancy that develops when leukocytes are produced abnormally, causing high levels of not properly functional white blood cells. Leukocytes include neutrophils, eosinophils, basophils, monocytes, and lymphocytes, all of which were shown to release extracellular traps. Acute leukemia patients have shown increased levels of NETs biomarkers [46][47] compared to healthy individuals. These findings suggest that aberrantly developed leukocytes, similar to fully functional leukocytes, could release extracellular traps in the circulation. That brings into question whether the release of extracellular traps could be utilized as a defense mechanism by the organism or as a progression mechanism by leukemic cells. Early studies suggested that the administration of extracellular H1 histone caused cytotoxicity in 19 of 21 leukemia-derived cell lines and 11 of 16 patient-derived tumor samples without affecting bone marrow cells and peripheral blood mononuclear cells [48]. Furthermore, histone H1 was able to inhibit tumor growth when injected into Burkitt’s lymphoma mouse model [48]. The effects of purified histones and NETs, which are composed of histones, DNA, and granule proteins, likely differ, especially due to the high toxicity of the positively charged free histones. It should be noted that a high concentration of purified histone H1 was used −200 µg/mLin cell lines and patient-derived tumor samples and 250 µg/mLin the mouse model. Conversely, later studies showed that cell-free histones in plasma samples of leukemia patients stimulated the attachment of leukemic cells to endothelial cells by inducing the expression of endothelial adhesion molecules. Furthermore, the histone-mediated adhering of leukemic cells to endothelial cells resulted in increased survival of leukemic cells to spontaneous and chemotherapy-induced death, directly linking extracellular histones to leukemia progression [46][47].
Several studies have shown drastically increased circulating histones and histone complexes in patients with hematologic malignancies [46][47][49][50][51]. Similarly, high levels of nucleosomes containing the histone H3.1 isoform (Nu.Q-H3.1) were found in non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), and especially in acute lymphocytic leukemia (ALL), with a median of 276 ng/mL, 284 ng/mL and 585 ng/mL, respectively, as compared to 40 ng/mL for healthy individuals [50]. Furthermore, Mueller et al. indicated that circulating histone complexes could act as a predictive marker of chemotherapy response in acute myeloid leukemia patients [52]. Levels of circulating nucleosomes were also found to correlate with lymphoma progression and detect advanced (stage III and IV) lymphoma with 100% sensitivity [53], which was subsequently suggested to be mediated irrespective of apoptosis [54]. Nevertheless, studies with large patient cohorts and advanced detection methods are lacking. Therefore, it is currently unlikely that histone level measurement and therapies modulating histone levels in hematologic malignancies could enter the clinics in the near future.

4. Circulating Histones in Solid Cancers: Detection, Monitoring, and Tumorigenesis

Diagnosis of solid cancers often requires biopsy acquisition through invasive procedures, which are frequently accompanied by time-consuming analysis. Furthermore, due to their invasive nature, traditional biopsies do not allow for interval testing and therefore lack disease-monitoring abilities. 

4.1. Cancer Detection

There is growing evidence that high nucleosome levels in the bloodstream are found among cancer patients, especially in advanced stages, which is not observed in healthy individuals [32][49][55][56][57][58][59]. Such nucleosome level increase was most notably observed in lung cancer patients and, to the lowest extent, in prostate cancer patients. Importantly, high levels of circulating nucleosomes were also detected in benign conditions, suggesting low diagnostics power [49]. Similarly, solely measuring the total level of nucleosomes in serum showed a weak ability to differentiate colorectal carcinoma (CRC) [60] from non-cancerous conditions. However, combining markers of epigenetically modified nucleosomes achieved high sensitivity and specificity of early-stage CRC detection [61][62]. Similarly, distinguishing stage II pancreatic cancer patients from healthy controls and benign disease through five histone-defined biomarkers detected in serum achieved a better prediction score, sensitivity, and specificity, compared to the common pancreatic tumor biomarker, carbohydrate antigen 19-9 (CA 19-9). Interestingly, out of the five marks were the histone variants H2AZ and mH2A1.1 [63], indicating that circulating histone variants could be attractive cancer biomarker candidates. Histone analysis by chromatin immunoprecipitation in the serum of colorectal, pancreatic, breast, and lung cancer patients revealed elevated levels of H3K9me3 and H4K20me3 in all cancer types compared to healthy individuals. Importantly, upon normalization of H3K9me3 and H4K20me3 levels to total nucleosome content, H3K9me3 and H4K20me3 were lower in CRC while remaining elevated in breast cancer compared to healthy controls. Comparing the two histone marks, H4K20me3 was found to discriminate cancer patients from healthy individuals when normalized to nucleosome value in patient serum, while total non-normalized H3K9me3 was able to distinguish colorectal cancer from non-cancerous gastrointestinal diseases [64]. Of note, ELISA-mediated detection of histone marks showed similar values for total H3K9me3 and decreased levels of total H4K20me3 and H3K27me3 in CRC patients compared to healthy individuals [65]. These findings suggest circulating histones as a valuable prognostic marker. However, it is evident that the results are influenced by both the detection method and the data analysis, indicating the need for appropriate standardization.
Recently, Vanderstichele et al. showed that the fragmentation of nucleosome-associated circulating plasma DNA predicted the presence of malignant tumors in 271 plasma samples from patients with an adnexal mass [30]. Of note, nucleosomal DNA fragmentation performed better at distinguishing ovarian cancer malignancies with low chromosomal instability than low-coverage whole genome sequencing [66]. The study suggests circulating plasma nucleosome-DNA complexes could serve as a complementary cancer detection approach, especially in subtypes with a low mutational burden. Similar findings were reported by Cristiano et al. for 236 patients diagnosed with breast, colorectal, lung, ovarian, pancreatic, gastric, or bile duct cancer [67]. Nucleosomal cfDNA fragmentation analysis achieved high sensitivity from 57% to more than 99% at 98% specificity among the analyzed cancer types. However, the model tested whether nucleosome positioning could distinguish cancer patients from healthy individuals, regardless of the cancer type [67]. It would be interesting to address whether the method could discriminate cancers with distinct origins, which could render circulating nucleosomes and nucleosome positioning a powerful tool in cancer care.

4.2. Treatment Guidance, Disease, and Therapy Response Monitoring

A limitation of measuring the total level of circulating nucleosomes as a cancer detection approach is the lack of specificity, as various cancer types have shown a high concentration of circulating nucleosomes in retrospective studies. Therefore, simply measuring nucleosomes in the blood lacks the ability to differentiate the primary origin or secondary metastases. However, that provides an opportunity to uncover minimal residual disease and treatment response in an easy-to-use and cost-effective manner. To ensure patients receive the most promising therapy, clinicians require parameters for patient stratification and prediction. Recently, the detection of two PTMs on H3 histone was shown to predict response to the kinase inhibitor sorafenib in hepatocellular carcinoma (HCC) patients. Specifically, increased H3K27me3/H3K36me3 ratio levels in plasma were associated with non-response to sorafenib and disease progression. Conversely, H3K27me3 and H3K36me3 levels were reduced in patients showing the best therapy response compared to baseline levels [68]. Low plasma H3K27me3 levels, but not general nucleosome levels, were also shown to distinguish metastatic prostate cancer from localized/locally advanced disease [69].
Increasing evidence suggests that circulating nucleosomes could be used in therapy response and disease monitoring in various solid cancer types. A transient increase in circulating nucleosome levels (6h and 24h post-treatment), followed by a consistent decrease, indicated positive chemotherapy and radiotherapy responses and remission. In contrast, nucleosome levels remained elevated or continued to rise in non-responder patients and were associated with disease progression [49][56][70][71][72][73][74][75][76]. In line with these findings, Gu et al. found that Radiofrequency ablation (RFA), which is often applied as first-line treatment in HCC patients, causes an increase in circulating histones within 24 h post-therapy [77]. Furthermore, Vanderstichele et al. showed that changes in nucleosome positioning footprint were able to detect anti-EGFR and anti-ERBB2 therapy responsiveness in non-small-cell lung cancer, as it closely reflected expression levels of EGFR or ERBB2 mutant alleles [67]. Similarly, Doebley et al. showed that nucleosome protection profiling could be applied for estrogen receptor subtyping in breast cancer [78]. Together, these findings strongly suggest that circulating histones and histone complexes hold great promise in treatment guidance and cancer monitoring.

4.3. Role in Disease Progression

As discussed, changes in circulating histones and histone complexes are prevalent among solid cancers and are associated with disease progression. However, whether and how such markers affect the growth and survival of cancer cells have not been researched elaborately.
Studies have shown the ability of the tumor environment to recruit neutrophils, which could further alter the microenvironment and stimulate tumor progression [79][80][81][82]. Szczerba et al. identified neutrophil-associated circulating tumor cells (CTCs) in breast cancer patients and murine models that displayed distinct transcriptomic compared to CTCs alone. Interestingly, differences in gene expression were most notably observed in metastasis-related cell cycle progression pathways, cell-cell junctions, and cytokine-receptor [83]. That brings into question the mechanisms utilized by neutrophils to alter CTC function.
Research by Lorenzo Ferri’s group suggested that extracellular traps facilitate the survival of circulating tumor cells, resulting in metastatic disease progression [84][85]. Utilizing in vivo mouse models and in vitro systems, the authors found that neutrophils are actively participating in metastasis initiation of H59 Lewis lung carcinoma cells and B16-F10 melanoma cells by inducing cell adhesion [84][85]. Metastatic initiation was diminished upon administration of DNAse 1 or neutrophil elastase inhibitor (NEi), directly linking NETs with disease progression. Of note, no histone inhibitors were used in the study [85]. It is plausible that histones are indirectly linked to tumor cell survival and metastasis. However, histones are a crucial component of NETs. Furthermore, real-time analysis via intravital microscopy imaging (IVM) showed tumor cell migration to histone-dense areas. Inhibitors of circulating histones could be used to elucidate the direct role of histones in cancer progression. The small polyanion methyl β-cellobioside per-O-sulfate (mCBS) specifically blocked histones while maintaining NETs integrity [86]. Recently, Wilson et al. showed that NETs could specifically induce the differentiation of IL-17-producing TH17 cells via histone recruitment to Toll-like receptor 2 (TLR2) on naïve T cells and downstream activation of STAT3. Following differentiation, TH17 cells cause further neutrophil activation, creating a positive feedback loop [87]. Given that Th17 T cells are associated with cancer progression [88][89][90], it could be hypothesized that histones exert a direct effect on tumorigenesis.

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Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Desislava K. Tsoneva , Martin N. Ivanov ,
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