The regulation of gene transcription by epigenetic modifications is closely related to many important life processes and is a hot research topic in the post-genomic era. Since the emergence of international epigenetic research in the 1990s, scientists have identified a variety of chromatin-modifying enzymes and recognition factors, and have systematically investigated their three-dimensional structures, substrate specificity, and mechanisms of enzyme activity regulation. Studies of the human tumor genome have revealed the close association of epigenetic factors with various malignancies, and we have focused more on mutations in epigenetically related regulatory enzymes and regulatory recognition factors in lymphomas. A number of studies have shown that epigenetic alterations are indeed widespread in the development and progression of lymphoma and understanding these mechanisms can help guide clinical efforts. In contrast to chemotherapy which induces cytotoxicity, epigenetic therapy has the potential to affect multiple cellular processes simultaneously, by reprogramming cells to achieve a therapeutic effect in lymphoma. Epigenetic monotherapy has shown promising results in previous clinical trials, and several epigenetic agents have been approved for use in the treatment of lymphoma. In addition, epigenetic therapies in combination with chemotherapy and/or immunotherapy have been used in various clinical trials. In this review, we present several important epigenetic modalities of regulation associated with lymphoma, summarize the corresponding epigenetic drugs in lymphoma, and look at the future of epigenetic therapies in lymphoma.

/pdf/the-status-and-prospects-of-epigenetics-in-the-treatment-of-2xxqef5b.pdf

The Status and Prospects of Epigenetics in the Treatment of Lymphoma

Blocking the de novo biosynthesis of pyrimidine by inhibiting human dihydroorotate dehydrogenase (hDHODH) is an effective way to suppress the proliferation of cancer cells and activated lymphocytes. Herein, eighteen teriflunomide derivatives and four ASLAN003 derivatives were designed and synthesized as novel hDHODH inhibitors based on a benzophenone scaffold. The optimal compound 7d showed a potent hDHODH inhibitory activity with an IC50 value of 10.9 nM, and displayed promising antiproliferative activities against multiple human cancer cells with IC50 values of 0.1–0.8 μM. Supplementation of exogenous uridine rescued the cell viability of 7d-treated Raji and HCT116 cells. Meanwhile, 7d significantly induced cell cycle S-phase arrest in Raji and HCT116 cells. Furthermore, 7d exhibited favorable safety profiles in mice and displayed effective antitumor activities with tumor growth inhibition (TGI) rates of 58.3% and 42.1% at an oral dosage of 30 mg/kg in Raji and HCT116 cells xenograft models, respectively. Taken together, these findings provide a promising hDHODH inhibitor 7d with potential activities against some tumors. 

Discovery of potent human dihydroorotate dehydrogenase inhibitors based on a benzophenone scaffold.

Simple Summary Canine malignant lymphoma is one of the most common neoplasias in dogs. Even though breed influences the prevalence and prognosis, most cases present resistance to traditional chemotherapy. Canine breeds such as Labrador and Golden Retriever often have a worse prognosis for this reason. This high resistance to anticancer drugs makes it necessary to search for other therapies and other therapeutic targets. In this sense, the epigenetic regulators of neoplasia could be a promising object of study in the search for new research advances. Abstract Canine malignant lymphoma is a common neoplasia in dogs, and some studies have used dogs as a research model for molecular mechanisms of lymphomas in humans. In two species, chemotherapy is the treatment of choice, but the resistance to conventional anticancer drugs is frequent. The knowledge of molecular mechanisms of development and progression of neoplasia has expanded in recent years, and the underlying epigenetic mechanisms are increasingly well known. These studies open up new ways of discovering therapeutic biomarkers. Histone deacetylases and demethylase inhibitors could be a future treatment for canine lymphoma, and the use of microRNAs as diagnosis and prognosis biomarkers is getting closer. This review summarises the epigenetic mechanisms underlying canine lymphoma and their possible application as treatment and biomarkers, both prognostic and diagnostic.

https://www.mdpi.com/2076-2615/13/3/468/pdf?version=1675311161

Epigenetic Alterations in Canine Malignant Lymphoma: Future and Clinical Outcomes

Abstract Dysregulation of various cells in the tumor microenvironment (TME) causes immunosuppressive functions and aggressive tumor growth. In combination with immune checkpoint blockade (ICB), epigenetic modification-targeted drugs are emerging as attractive cancer treatments. Lysine-specific demethylase 1 (LSD1) is a protein that modifies histone and non-histone proteins and is known to influence a wide variety of physiological processes. The dysfunction of LSD1 contributes to poor prognosis, poor patient survival, drug resistance, immunosuppression, etc., making it a potential epigenetic target for cancer therapy. This review examines how LSD1 modulates different cell behavior in TME and emphasizes the potential use of LSD1 inhibitors in combination with ICB therapy for future cancer research studies. 

LSD1: an emerging face in altering the tumor microenvironment and enhancing immune checkpoint therapy

Histones are the main components of chromatin, functioning as an instructive scaffold to maintain chromosome structure and regulate gene expression. The dysregulation of histone modification is associated with various pathological processes, especially cancer initiation and development, and histone methylation plays a critical role. However, the specific mechanisms and potential therapeutic targets of histone methylation in cancer are not elucidated. Lys-specific demethylase 1A (LSD1) was the first identified demethylase that specifically removes methyl groups from histone 3 at lysine 4 or lysine 9, acting as a repressor or activator of gene expression. Recent studies have shown that LSD1 promotes cancer progression in multiple epigenetic regulation or non-epigenetic manners. Notably, LSD1 dysfunction is correlated with repressive cancer immunity. Many LSD1 inhibitors have been developed and clinical trials are exploring their efficacy in monotherapy, or combined with other therapies. In this review, we summarize the oncogenic mechanisms of LSD1 and the current applications of LSD1 inhibitors. We highlight that LSD1 is a promising target for cancer treatment. This review will provide the latest theoretical references for further understanding the research progress of oncology and epigenetics, deepening the updated appreciation of epigenetics in cancer. 

Targeting LSD1 in cancer: molecular elucidation and recent advances

Lysine-specific demethylase 1 (LSD1, also known as KDM1A) is an attractive agent for treatment of cancer. However, the anti-tumor effect of LSD1 inhibitors against diffuse large B-cell lymphoma (DLBCL) and the underlying mechanism are still unclear. Here, we report that KDM1A is overexpressed in human DLBCL tissues and negatively related to overall survival rate of DLBCL patients. ZY0511, a novel and potent LSD1 inhibitor developed by our group, inhibited the proliferation of human DLBCL cells. ZY0511 interacted with LSD1, induced methylation level of histone 3 lysine 4 and histone 3 lysine 9 in DLBCL cells. Mechanistically, transcriptome sequencing results indicated that ZY0511 induced the genes enrichment significantly related to cell cycle, autophagy, and apoptosis signaling pathways. Further study confirmed that ZY0511 blocked cell cycle at G0/G1 phase and expression of CDK4 and cyclin D1. ZY0511 decreased mitochondrial membrane potential and induced apoptosis, which can be reverted by a pan-caspase inhibitor, Z-VAD-FMK. Moreover, ZY0511 treatment significantly increased autophagy-associated marker proteins and autophagosomes formation in DLBCL cells. In vivo xenograft experiments confirmed that intraperitoneal administration of ZY0511 significantly suppressed SU-DHL-6 xenograft tumor growth in vivo. In conclusion, our findings identify that ZY0511 inhibits DLBCL growth both in vitro and in vivo via the induction of apoptosis and autophagy, and LSD1 inhibitor might be a promising strategy for treating DLBCL.

/pdf/the-novel-lsd1-inhibitor-zy0511-suppresses-diffuse-large-b-238ivxqlp1.pdf

The novel LSD1 inhibitor ZY0511 suppresses diffuse large B-cell lymphoma proliferation by inducing apoptosis and autophagy

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The novel LSD1 inhibitor ZY0511 suppresses diffuse large B-cell lymphoma proliferation by inducing apoptosis and autophagy