Epigenetic dysregulation is a common feature of a myriad of human diseases, particularly cancer. Defining the epigenetic defects associated with malignant tumors has become a focus of cancer research resulting in the gradual elucidation of cancer cell epigenetic regulation. In fact, most stages of tumor progression, including tumorigenesis, promotion, progression, and recurrence are accompanied by epigenetic alterations, some of which can be reversed by epigenetic drugs. The main objective of epigenetic therapy in the era of personalized precision medicine is to detect cancer biomarkers to improve risk assessment, diagnosis, and targeted treatment interventions. Rapid technological advancements streamlining the characterization of molecular epigenetic changes associated with cancers have propelled epigenetic drug research and development. This review summarizes the main mechanisms of epigenetic dysregulation and discusses past and present examples of epigenetic inhibitors in cancer diagnosis and treatment, with an emphasis on the development of epigenetic enzyme inhibitors or drugs. In the final part, the prospect of precise diagnosis and treatment is considered based on a better understanding of epigenetic abnormalities in cancer. 

Cancer epigenetics: from laboratory studies and clinical trials to precision medicine

Abstract The development and immune evasion of cancer stem cells (CSCs) limit the efficacy of currently available anticancer therapies. Recent studies have shown that epigenetic reprogramming regulates the expression of characteristic marker proteins and tumor plasticity associated with cancer cell survival and metastasis in CSCs. CSCs also possess unique mechanisms to evade external attacks by immune cells. Hence, the development of new strategies to restore dysregulated histone modifications to overcome cancer resistance to chemotherapy and immunotherapy has recently attracted attention. Restoring abnormal histone modifications can be an effective anticancer strategy to increase the therapeutic effect of conventional chemotherapeutic and immunotherapeutic drugs by weakening CSCs or by rendering them in a naïve state with increased sensitivity to immune responses. In this review, we summarize recent findings regarding the role of histone modifiers in the development of drug-resistant cancer cells from the perspectives of CSCs and immune evasion. In addition, we discuss attempts to combine currently available histone modification inhibitors with conventional chemotherapy or immunotherapy. 

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Histone modifications in drug-resistant cancers: From a cancer stem cell and immune evasion perspective.

There is increasing evidence that malignant tumors are initiated and maintained by a sub-population of tumor cells that have similar biological properties to normal adult stem cells. This very small population of Cancer Stem Cells (CSC) comprises tumor initiating cells responsible for cancer recurrence, drug resistance and metastasis. Conventional treatments such as chemotherapy, radiotherapy and surgery, in addition to being potentially toxic and non-specific, may paradoxically increase the population, spread and survival of CSCs. Next-generation sequencing and omics technologies are increasing our understanding of the pathways and factors involved in the development of CSCs, and can help to discover new therapeutic targets against CSCs. In addition, recent advances in nanomedicine have provided hope for the development of optimal specific therapies to eradicate CSCs. Moreover, the use of artificial intelligence and nano-informatics can elucidate new drug targets, and help to design drugs and nanoparticles (NPs) to deal with CSCs. In this review, we first summarize the properties of CSCs and describe the signaling pathways and molecular characteristics responsible for the emergence and survival of CSCs. Also, the location of CSCs within the tumor and the effect of host factors on the creation and maintenance of CSCs are discussed. Newly discovered molecular targets involved in cancer stemness and some novel therapeutic compounds to combat CSCs are highlighted. The optimum properties of anti-CSC NPs, including blood circulation and stability, tumor accumulation and penetration, cellular internalization, drug release, endosomal escape, and aptamers designed for specific targeting of CSCs are covered. Finally, some recent smart NPs designed for therapeutic and theranostic purposes to overcome CSCs are discussed. 

Molecular targets, therapeutic agents and multitasking nanoparticles to deal with cancer stem cells: A narrative review.

Histone lysine methylation is a post-translational modification that plays a key role in the epigenetic regulation of a broad spectrum of biological processes. Moreover, the dysregulation of histone lysine methyltransferases (KMTs) has been implicated in the pathogenesis of several diseases particularly cancer. Due to their pathobiological importance, KMTs have garnered immense attention over the last decade as attractive therapeutic targets. These endeavors have culminated in tens of chemical probes that have been used to interrogate many aspects of histone lysine methylation. Besides, over a dozen inhibitors have been advanced to clinical trials, including the EZH2 inhibitor tazemetostat approved for the treatment of follicular lymphoma and advanced epithelioid sarcoma. In this Review, we highlight the chemical biology and pharmacology of KMT inhibitors and targeted protein degraders focusing on the clinical development of EZH1/2, DOT1L, Menin-MLL, and WDR5-MLL inhibitors. We also briefly discuss the pharmacologic targeting of other KMTs. 

Chemical biology and pharmacology of histone lysine methylation inhibitors.

Epigenetic regulation refers to the alteration of gene expression independent of changes in DNA sequence. It involves chemical modifications such as DNA methylation, histone methylation, and histone acetylation, which are regulated by a coordinated interplay of various regulators to ensure precise spatial and temporal regulation of gene expression. Epigenetic aberrations are commonly observed in cancer and are considered as hallmarks of cancer. In recent years, small molecules targeting specific epigenetic regulators have been developed and are demonstrating promising therapeutic potential in preclinical and clinical trials for cancer treatment. In this review, we summarize the essential regulatory mechanisms and dysfunctions of epigenetic regulators involved in DNA methylation, histone methylation, and histone acetylation during tumor development and progression. Moreover, we discuss the current advances and challenges in cancer epigenetic therapy that target these mechanisms in both hematologic malignancies and solid tumors. Finally, we discuss the potential of combining epigenetic drugs with other therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, as a promising approach for cancer treatment. Overall, we aim to enhance the understanding of epigenetic regulation in cancer therapy and explore targeted therapeutic strategies based on these mechanisms, to ultimately advance cancer therapy and improve patient prognosis.

Epigenetic regulation in cancer therapy: From mechanisms to clinical advances

Although chemotherapies kill most cancer cells, stem cell-enriched survivors seed metastasis, particularly in triple-negative breast cancers (TNBC). TNBCs arise from and are enriched for tumor stem cells. Here, we tested if inhibition of DOT1L, an epigenetic regulator of normal tissue stem/progenitor populations, would target TNBC stem cells.Effects of DOT1L inhibition by EPZ-5676 on stem cell properties were tested in three TNBC lines and four patient-derived xenograft (PDX) models and in isolated cancer stem cell (CSC)-enriched ALDH1+ and ALDH1- populations. RNA sequencing compared DOT1L regulated pathways in ALDH1+ and ALDH1- cells. To test if EPZ-5676 decreases CSC in vivo, limiting dilution assays of EPZ-5676/vehicle pretreated ALDH1+ and ALDH1- cells were performed. Tumor latency, growth, and metastasis were evaluated. Antitumor activity was also tested in TNBC PDX and PDX-derived organoids.ALDH1+ TNBC cells exhibit higher DOT1L and H3K79me2 than ALDH1-. DOT1L maintains MYC expression and self-renewal in ALDH1+ cells. Global profiling revealed that DOT1L governs oxidative phosphorylation, cMyc targets, DNA damage response, and WNT activation in ALDH1+ but not in ALDH1- cells. EPZ-5676 reduced tumorspheres and ALDH1+ cells in vitro and decreased tumor-initiating stem cells and metastasis in xenografts generated from ALDH1+ but not ALDH1- populations in vivo. EPZ-5676 significantly reduced growth in vivo of one of two TNBC PDX tested and decreased clonogenic 3D growth of two other PDX-derived organoid cultures.DOT1L emerges as a key CSC regulator in TNBC. Present data support further clinical investigation of DOT1L inhibitors to target stem cell-enriched TNBC. 

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DOT1L Is a Novel Cancer Stem Cell Target for Triple-Negative Breast Cancer

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DOT1L Is a Novel Cancer Stem Cell Target for Triple-Negative Breast Cancer