Small-Molecule Inhibitors Overcome Epigenetic Reprogramming for Cancer Therapy

Xiao, Wenjing; Zhou, Qin; Wen, Xudong; Wang, Rui; Liu, Ruijie; Wang, Tingting; Shi, Jianyou; Hu, Yonghe; Hou, Jing

doi:10.3389/fphar.2021.702360

Cited by 22 publications

(15 citation statements)

References 192 publications

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“…Our study identifies small molecule epigenetic drugs that activate autophagy in mESCs. Epigenetic inhibitors have emerged as promising therapeutic alternatives to cytotoxic drug regimens [68]. Thus the identification of novel regulatory mechanisms for cytoprotective pathways such as autophagy not only provides an enhanced understanding of the role of autophagy in stemness and differentiation, but also facilitates new avenues into developing druggable treatment paradigms to combat autophagy-mediated disorders.…”

Section: Discussionmentioning

confidence: 99%

Autophagy-cell death balance is maintained by Polycomb-mediated regulation during stem cell differentiation

Puri

Kelkar

Bhaskar

et al. 2022

Preprint

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Autophagy is a conserved cytoprotective process, aberrations in which, lead to numerous degenerative disorders. While the cytoplasmic components of autophagy have been extensively studied, the epigenetic regulation of autophagy genes, especially in stem cells, is less understood. Deciphering the epigenetic regulation of autophagy genes becomes increasingly relevant given the therapeutic benefits of small-molecule epigenetic inhibitors in novel treatment modalities. We observe that, during retinoic acid-mediated differentiation of mouse embryonic stem cells (mESCs), autophagy is induced, and identify the Polycomb enzyme EZH2 as a regulator of this process. In mESCs, EZH2 represses several autophagy genes including the autophagy regulator Dram1. EZH2 facilitates the formation of a bivalent chromatin domain at the Dram1 promoter, which allows the expression of the gene and induction of autophagy during differentiation, while still retaining the repressive H3K27me3 mark. EZH2 inhibition leads to loss of the bivalent domain, and a consequential “hyper- expression” of Dram1, with extensive cell death. This study shows that Polycomb group proteins help maintain an autophagy-cell death balance during stem cell differentiation, in part, by regulating the expression of the Dram1 gene.

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Section: Discussionmentioning

confidence: 99%

Autophagy-cell death balance is maintained by Polycomb-mediated regulation during stem cell differentiation

Puri

Kelkar

Bhaskar

et al. 2022

Preprint

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“…Similarly, understanding the contribution of epigenetic mechanisms to the control of Treg cell suppressive capacity is also relevant. Particularly as several small-molecule epigenetic modifiers are FDA approved and utilized in the clinic (279). Hypomethylating agents, inhibitors of histone deacetylases, and bromodomain inhibitors are all relevant in this context.…”

Section: Future Directionsmentioning

confidence: 99%

Colorectal Cancer-Infiltrating Regulatory T Cells: Functional Heterogeneity, Metabolic Adaptation, and Therapeutic Targeting

2022

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Colorectal cancer (CRC) is a heterogeneous disease with one of the highest rates of incidence and mortality among cancers worldwide. Understanding the CRC tumor microenvironment (TME) is essential to improve diagnosis and treatment. Within the CRC TME, tumor-infiltrating lymphocytes (TILs) consist of a heterogeneous mixture of adaptive immune cells composed of mainly anti-tumor effector T cells (CD4+ and CD8+ subpopulations), and suppressive regulatory CD4+ T (Treg) cells. The balance between these two populations is critical in anti-tumor immunity. In general, while tumor antigen-specific T cell responses are observed, tumor clearance frequently does not occur. Treg cells are considered to play an important role in tumor immune escape by hampering effective anti-tumor immune responses. Therefore, CRC-tumors with increased numbers of Treg cells have been associated with promoting tumor development, immunotherapy failure, and a poorer prognosis. Enrichment of Treg cells in CRC can have multiple causes including their differentiation, recruitment, and preferential transcriptional and metabolic adaptation to the TME. Targeting tumor-associated Treg cell may be an effective addition to current immunotherapy approaches. Strategies for depleting Treg cells, such as low-dose cyclophosphamide treatment, or targeting one or more checkpoint receptors such as CTLA-4 with PD-1 with monoclonal antibodies, have been explored. These have resulted in activation of anti-tumor immune responses in CRC-patients. Overall, it seems likely that CRC-associated Treg cells play an important role in determining the success of such therapeutic approaches. Here, we review our understanding of the role of Treg cells in CRC, the possible mechanisms that support their homeostasis in the tumor microenvironment, and current approaches for manipulating Treg cells function in cancer.

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“…The significant advancement of work on other SMIs, including on-going clinical trials, causes the implementation of new drugs is a matter of time. However, at present the use of SMIs in clinical settings is mostly limited to hematological malignancies (300)(301)(302). Safety issues related mostly to the lack of selectivity produce significant limitations with implementation of SMIs.…”

Section: Normalization Of T-cell Function As a Target For Novel Epige...mentioning

confidence: 99%

Epigenetic regulation and T-cell responses in endometriosis – something other than autoimmunity

Szukiewicz

2022

Front. Immunol.

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Endometriosis is defined as the presence of endometrial-like glands and stroma located outside the uterine cavity. This common, estrogen dependent, inflammatory condition affects up to 15% of reproductive-aged women and is a well-recognized cause of chronic pelvic pain and infertility. Despite the still unknown etiology of endometriosis, much evidence suggests the participation of epigenetic mechanisms in the disease etiopathogenesis. The main rationale is based on the fact that heritable phenotype changes that do not involve alterations in the DNA sequence are common triggers for hormonal, immunological, and inflammatory disorders, which play a key role in the formation of endometriotic foci. Epigenetic mechanisms regulating T-cell responses, including DNA methylation and posttranslational histone modifications, deserve attention because tissue-resident T lymphocytes work in concert with organ structural cells to generate appropriate immune responses and are functionally shaped by organ-specific environmental conditions. Thus, a failure to precisely regulate immune cell transcription may result in compromised immunological integrity of the organ with an increased risk of inflammatory disorders. The coexistence of endometriosis and autoimmunity is a well-known occurrence. Recent research results indicate regulatory T-cell (Treg) alterations in endometriosis, and an increased number of highly active Tregs and macrophages have been found in peritoneal fluid from women with endometriosis. Elimination of the regulatory function of T cells and an imbalance between T helper cells of the Th1 and Th2 types have been reported in the endometria of women with endometriosis-associated infertility. This review aims to present the state of the art in recognition epigenetic reprogramming of T cells as the key factor in the pathophysiology of endometriosis in the context of T-cell-related autoimmunity. The new potential therapeutic approaches based on epigenetic modulation and/or adoptive transfer of T cells will also be outlined.

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Small-Molecule Inhibitors Overcome Epigenetic Reprogramming for Cancer Therapy

Cited by 22 publications

References 192 publications

Autophagy-cell death balance is maintained by Polycomb-mediated regulation during stem cell differentiation

Autophagy-cell death balance is maintained by Polycomb-mediated regulation during stem cell differentiation

Colorectal Cancer-Infiltrating Regulatory T Cells: Functional Heterogeneity, Metabolic Adaptation, and Therapeutic Targeting

Epigenetic regulation and T-cell responses in endometriosis – something other than autoimmunity

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