Disruption of SIRT7 Increases the Efficacy of Checkpoint Inhibitor via MEF2D Regulation of Programmed Cell Death 1 Ligand 1 in Hepatocellular Carcinoma Cells

Xiang, Junyu; Zhang, Ni; Sun, Hui; Su, Li; Zhang, Chengcheng; Xu, Huailong; Feng, Juan; Wang, Meiling; Chen, Jun; Liu, Limei; Shan, Juanjuan; Shen, Junjie; Yang, Zhi; Wang, Guiqin; Zhou, Haijun; Prìeto, Jesús; Ávila, Matías A.; Liu, Chungang; Qian, Cheng

doi:10.1053/j.gastro.2019.10.025

Cited by 77 publications

(64 citation statements)

References 47 publications

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“… 151 A recent study also provided a rationale for SIRT7 inhibition to increase the efficacy of immunotherapy (anti PD-L1) in mouse models, however potent and specific SIRT7 small molecule inhibitors still need to be synthesised. 152 …”

Section: Targeting Epigenetic Mechanisms In Hccmentioning

confidence: 99%

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

et al. 2020

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Summary Hepatocellular carcinoma (HCC) is a deadly tumour whose causative agents are generally well known, but whose pathogenesis remains poorly understood. Nevertheless, key genetic alterations are emerging from a heterogeneous molecular landscape, providing information on the tumorigenic process from initiation to progression. Among these molecular alterations, those that affect epigenetic processes are increasingly recognised as contributing to carcinogenesis from preneoplastic stages. The epigenetic machinery regulates gene expression through intertwined and partially characterised circuits involving chromatin remodelers, covalent DNA and histone modifications, and dedicated proteins reading these modifications. In this review, we summarise recent findings on HCC epigenetics, focusing mainly on changes in DNA and histone modifications and their carcinogenic implications. We also discuss the potential drugs that target epigenetic mechanisms for HCC treatment, either alone or in combination with current therapies, including immunotherapies.

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Section: Targeting Epigenetic Mechanisms In Hccmentioning

confidence: 99%

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

et al. 2020

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“…Several sirtuin family members, such as SIRT1, SIRT2, and SIRT6, can regulate NF-kB-driven immune responses through the protein deacetylation. Recent research demonstrated that SIRT7 can inhibit the expression of PD-L1 though reducing acetylation of MEF2D in hepatocellular carcinoma cells not exposed to interferon gamma [161]. The PD-L1 expression of cancer cells can bind to PD1 on CD8 + T cells, which may prevent T cell proliferation and reduce their anti-tumor immunity response.…”

Section: Sirtuins and Cancer Immunotherapymentioning

confidence: 99%

The Roles of Sirtuin Family Proteins in Cancer Progression

Zhao

Hou

et al. 2019

Cancers

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Sirtuin family members are characterized by either mono-ADP-ribosyltransferase or deacylase activity and are linked to various cancer-related biological pathways as regulators of transcriptional progression. Sirtuins play fundamental roles in carcinogenesis and maintenance of the malignant phenotype, mainly participating in cancer cell viability, apoptosis, metastasis, and tumorigenesis. Although sirtuin family members have a high degree of homology, they may play different roles in various kinds of cancer. This review highlights their fundamental roles in tumorigenesis and cancer development and provides a critical discussion of their dual roles in cancer, namely, as tumor promoters or tumor suppressors.

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“…PD-L1 is typically expressed on tumor cells, enabling them to inhibit PD-1 + T cell function thereby enhancing the ability of tumors to escape the immune system [22][23]. Up-regulation of PD-L1 in HCC cells is associated with poor prognosis, which is a potential marker for poor prognosis and recurrence of liver cancer [24][25]. Furthermore, PD-L1 is expressed not only on tumor cells but also on immune cells such as NK cells, dendritic cells, and T cells within the tumor microenvironment [15,[26][27].…”

Section: Discussionmentioning

confidence: 99%

Berberine enhances the anti-HCC effect of NK cells through inhibiting interferon-gamma-mediated PD-L1 expression

Wang¹,

Gu²,

Yu³

et al. 2021

Preprint

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Berberine (BBR) is an isoquinoline alkaloid with various functions in anti-inflammation, blocking tumor immune escape and enhancing the anti-tumor activity of immune cells. However, its immunomodulatory effect on natural killer (NK) cell activity in Hepatocellular carcinoma (HCC) is still unclear. Here, we determined whether BBR enhances the anti-HCC effect of NK cells and its mechanism by focusing on the regulation of the Programmed death-ligand 1 (PD-L1) pathway. It was found that BBR enhanced the cytotoxicity of NK92-MI cells to HCC cells in vitro and in vivo. The combination of BBR and PBMCs inhibited the proliferation and induced the apoptosis of HCC cells. BBR increased the frequency of CD3−CD56+ and CD3−CD16+ NK cells in peripheral blood isolated from healthy volunteers. Furthermore, the expression of PD-L1 in HCC cells was up-regulated after co-culture with NK-92MI cells or PBMCs. PD-L1 knockdown increased the sensitivity of HCC cells to NK-92MI cells and PBMCs. Mechanisms for BBR blocked the secretion of Interferon Gamma (IFN-γ), thereby inhibiting PD-L1 expression caused by the interaction of NK92-MI cells/PBMCs and HCC cells. Collectively, we are the first to demonstrate that BBR plays an immunomodulatory role by enhancing the cytotoxic effect of NK cells and inhibiting tumor immune escape by reducing the expression of PD-L1. Our study provides a theoretical basis for the clinical application of BBR combined with NK cells in the treatment of HCC.

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Disruption of SIRT7 Increases the Efficacy of Checkpoint Inhibitor via MEF2D Regulation of Programmed Cell Death 1 Ligand 1 in Hepatocellular Carcinoma Cells

Cited by 77 publications

References 47 publications

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

The Roles of Sirtuin Family Proteins in Cancer Progression

Berberine enhances the anti-HCC effect of NK cells through inhibiting interferon-gamma-mediated PD-L1 expression

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