Abstract
BackgroundDysregulation in post-translational modifications of histones and their modifiers are now well-recognized as a hallmark of cancer and can be used as biomarkers and potential therapeutic targets for disease progression and prognosis. In most solid tumours, a biopsy is challenging, costly, painful or potentially risky for the patient. Therefore, non-invasive methods like ‘liquid biopsy’ for analysis of histone modifications and their modifiers if possible will be helpful in the better clinical management of cancer patients.MethodsHere, we have developed a cost-effective and time-efficient protocol for isolation of circulating histones from serum of solid tumor, HCC, called Dual Acid Extraction (DAE) protocol and have confirmed by mass spectrometry. Also, we measured the activity of HDACs and HATs in serum samples.ResultsThe serum purified histones were profiled for changes in histone PTMs and have shown a comparable pattern of modifications like acetylation (H4K16Ac), methylation (H4K20Me3, H3K27Me3, H3K9Me3) and phosphorylation (γ-H2AX and H3S10P) to paired cancer tissues. Profiling for the histone PTM changes in various other organs of normal and tumor bearing animal suggests that the changes in the histone PTMs observed in the tumor serum is indeed due to changes in the tumor tissue only. Further, we demonstrate that the observed hypo-acetylation of histone H4 in tissue and serum samples of tumor bearing animals corroborated with the elevated HDAC activity in both samples compared to normal. Interestingly, human normal and tumor serum samples also showed elevated HDAC activity with no significant changes in HAT activity.ConclusionsOur study provides the first evidence in the context of histone PTMs and modifiers that liquid biopsy is a valuable predictive tool for monitoring disease progression. Importantly, with the advent of drugs that target specific enzymes involved in the epigenetic regulation of gene expression, liquid biopsy-based ‘real time’ monitoring will be useful for subgrouping of the patients for epi-drug treatment, predicting response to therapy, early relapse and prognosis.
Highlights
Dysregulation in post-translational modifications of histones and their modifiers are wellrecognized as a hallmark of cancer and can be used as biomarkers and potential therapeutic targets for disease progression and prognosis
Decades of research have discovered a battery of histone post-translational modifications (PTMs) that are altered in cancer and are referred as ‘histone onco-modifications’, but none has reached clinics primarily due to technological limitations in the diagnosis of solid tumours
Isolation of serum histones We developed a minimally invasive and cost effective, robust protocol for isolation of histones from serum samples
Summary
Dysregulation in post-translational modifications of histones and their modifiers are wellrecognized as a hallmark of cancer and can be used as biomarkers and potential therapeutic targets for disease progression and prognosis. Decades of research have discovered a battery of histone PTMs that are altered in cancer and are referred as ‘histone onco-modifications’, but none has reached clinics primarily due to technological limitations in the diagnosis of solid tumours. Cancer diagnosis and staging of solid tumours are done with an imaging technique followed by a surgical biopsy. Diagnosis or monitoring of solid tumours utilizing circulating epigenetic biomarkers in blood samples, if possible, will prove to be a very powerful tool and will overcome all the earlier limitations. Research conducted over the last few years has identified and detected epigenetic biomarkers associated with cancer, including aberrant DNA methylation patterns, miRNA profiles and histone signatures in body fluids of the patients [6, 7]
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