HDAC1/3-dependent moderate liquid–liquid phase separation of YY1 promotes METTL3 expression and AML cell proliferation

Meng, Li; Li, Mingying; Xia, Yuan; Li, Guosheng; Su, Xiuhua; Wang, Dongmei; Ye, Jingjing; Lü, Fei; Sun, Tao; Ji, Chunyan

doi:10.1038/s41419-022-05435-y

Cited by 14 publications

(15 citation statements)

References 57 publications

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“…Finally, we compared leukemic activated hematopoietic stem cells (HSCs) to their dormant counterparts categorized by mutational burden through CloneTrace (28). Using both M2Kb and ChIP-Atlas-based blood regulons (GM-12878 and K-562), we identified dysregulation in essential transcription factors involved in hematopoiesis and AML progression, such as MYB (51), MYC (52), SP1 (53), CREB1 (54) and YY1 (55) in activated leukemic HSCs (Fig. S8D).…”

Section: Resultsmentioning

confidence: 99%

Specifying cellular context of transcription factor regulons for exploring context-specific gene regulation programs

Minaeva,

Domingo,

Rentzsch

et al. 2024

Preprint

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Understanding the role of transcription and transcription factors in cellular identity and disease, such as cancer and autoimmunity, is essential. However, comprehensive data resources for cell line-specific transcription factor-to-target gene annotations are currently limited. To address this, we developed a straightforward method to define regulons that capture the cell-specific aspects of TF binding and transcript expression levels. By integrating cellular transcriptome and transcription factor binding data, we generated regulons for four common cell lines comprising both proximal and distal cell line-specific regulatory events. Through systematic benchmarking involving transcription factor knockout experiments, we demonstrated performance on par with state-of-the-art methods, with our method being easily applicable to other cell types of interest. We present case studies using three cancer single-cell datasets to showcase the utility of these cell-type-specific regulons in exploring transcriptional dysregulation. In summary, this study provides a valuable tool and a resource for systematically exploring cell line-specific transcriptional regulations, emphasizing the utility of network analysis in deciphering disease mechanisms.

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Section: Resultsmentioning

confidence: 99%

Specifying cellular context of transcription factor regulons for exploring context-specific gene regulation programs

Minaeva,

Domingo,

Rentzsch

et al. 2024

Preprint

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“…EMT dysregulation contributes to cancer metastasis through the disruption of cell–cell adhesion and the promotion of a migratory cellular state [ 51 , 66 , 71 ]. Another factor implicated with YY1 is the TF specificity protein 1 (Sp1), which acts as a coactivator to form a YY1-Sp1 complex [ 56 , 72 ]. This initiates the transcription of the mu opioid receptor ( MOR ) gene in human lymphocytes [ 56 , 72 ].…”

Section: Yy1 Overexpression In Cancer Oncogenic and Immunosuppressive...mentioning

confidence: 99%

“…Another factor implicated with YY1 is the TF specificity protein 1 (Sp1), which acts as a coactivator to form a YY1-Sp1 complex [ 56 , 72 ]. This initiates the transcription of the mu opioid receptor ( MOR ) gene in human lymphocytes [ 56 , 72 ]. The activation of MOR causes the suppression of lymphocyte proliferation.…”

Section: Yy1 Overexpression In Cancer Oncogenic and Immunosuppressive...mentioning

confidence: 99%

“…In B-cell lymphoma, inhibition of HDAC3 was shown to upregulate PD-L1 transcription [ 183 ], and in another study on lung cancer in mice, inhibition of HDAC6 was shown to decrease PD-L1 mRNA and protein levels [ 184 ]. Furthermore, YY1 has been confirmed to regulate and interact with several HDACs [ 72 , 185 ]. In acute myeloid leukemia (AML) cells, YY1 was revealed to bind and interact with HDAC1/3 [ 185 ].…”

Section: Regulation Of Pd-l1 By Yy1mentioning

confidence: 99%

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Regulation of PD-L1 Expression by YY1 in Cancer: Therapeutic Efficacy of Targeting YY1

Dillen,

Bui,

Jung

et al. 2024

Cancers

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During the last decade, we have witnessed several milestones in the treatment of various resistant cancers including immunotherapeutic strategies that have proven to be superior to conventional treatment options, such as chemotherapy and radiation. This approach utilizes the host’s immune response, which is triggered by cancer cells expressing tumor-associated antigens or neoantigens. The responsive immune cytotoxic CD8+ T cells specifically target and kill tumor cells, leading to tumor regression and prolongation of survival in some cancers; however, some cancers may exhibit resistance due to the inactivation of anti-tumor CD8+ T cells. One mechanism by which the anti-tumor CD8+ T cells become dysfunctional is through the activation of the inhibitory receptor programmed death-1 (PD-1) by the corresponding tumor cells (or other cells in the tumor microenvironment (TME)) that express the programmed death ligand-1 (PD-L1). Hence, blocking the PD-1/PD-L1 interaction via specific monoclonal antibodies (mAbs) restores the CD8+ T cells’ functions, leading to tumor regression. Accordingly, the Food and Drug Administration (FDA) has approved several checkpoint antibodies which act as immune checkpoint inhibitors. Their clinical use in various resistant cancers, such as metastatic melanoma and non-small-cell lung cancer (NSCLC), has shown significant clinical responses. We have investigated an alternative approach to prevent the expression of PD-L1 on tumor cells, through targeting the oncogenic transcription factor Yin Yang 1 (YY1), a known factor overexpressed in many cancers. We report the regulation of PD-L1 by YY1 at the transcriptional, post-transcriptional, and post-translational levels, resulting in the restoration of CD8+ T cells’ anti-tumor functions. We have performed bioinformatic analyses to further explore the relationship between both YY1 and PD-L1 in cancer and to corroborate these findings. In addition to its regulation of PD-L1, YY1 has several other anti-cancer activities, such as the regulation of proliferation and cell viability, invasion, epithelial–mesenchymal transition (EMT), metastasis, and chemo-immuno-resistance. Thus, targeting YY1 will have a multitude of anti-tumor activities resulting in a significant obliteration of cancer oncogenic activities. Various strategies are proposed to selectively target YY1 in human cancers and present a promising novel therapeutic approach for treating unresponsive cancer phenotypes. These findings underscore the distinct regulatory roles of YY1 and PD-L1 (CD274) in cancer progression and therapeutic response.

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“…The m 6 A modification of RNA has been shown to be strongly related to tumorigenesis 22–28 . Proteins of the m 6 A methyltransferase complex METTL3, METTL14, WTAP and VIRMA are mostly upregulated in cancer cells and tissues and act as oncogenes by regulating various signaling pathways in different types of cancers, including acute myeloid leukemia (AML) 29–33 , hepatocellular carcinoma, colorectal cancer 34 , gastric cancer 35,36 , lung cancer 37,38 , bladder cancer 39 , breast cancer 40 , prostate cancer 41 , skin cancer 42 , endometrial cancer 43 , renal cell carcinoma 44 , pancreatic cancer 34,45 , oral cancer 46 and melanoma 47 . In contrast, it has been indicated that the overexpression of METTL3 or inhibition of the RNA demethylase FTO suppresses glioblastoma stem cell growth and self-renewal 48 .…”

Section: Introductionmentioning

confidence: 99%

Novel RNA m⁶A methyltransferase METTL16 inhibitors

Selberg

Ivanova

Kotli

et al. 2023

Preprint

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The overexpression of RNA 6-N-methyladenosine (m6A) methyltransferase METTL16 has oncogenic role in the case of several cancer types, including leukemia, but efficient small-molecule inhibitors are not available. Initially identified by high-throughput virtual screening of the ZINC15 database in vivo subset, but then confirmed by measuring catalytic activity, two nanomolar-active METTL16 inhibitors, compounds 1 (IC50 = 25.82 ± 17.19 nM) and 2 (IC50 = 60.91 ± 2.75 nM) were found. The inhibitory activity of the compounds was measured using the m6A antibody-based ELISA assay. We also present the results on the effect of these inhibitors on the viability of promyeloblast HL-60 and lymphoblast CCRF-CEM leukemia cell lines. In unstressed growth conditions, both identified METTL16 inhibitors reduced the viability of HL-60 cells by up to 40%. The effect on the viability of CCRF-CEM cells was smaller with no dose dependency observed. In parallel, the level of the m6A as compared to unmodified adenosine in the HL-60 cell mRNAs was significantly reduced by the inhibitor 1. Collectively, we herein demonstrate novel METTL16 inhibitors that exert tumor cell-lineage-selective antiproliferative effects.

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HDAC1/3-dependent moderate liquid–liquid phase separation of YY1 promotes METTL3 expression and AML cell proliferation

Cited by 14 publications

References 57 publications

Specifying cellular context of transcription factor regulons for exploring context-specific gene regulation programs

Specifying cellular context of transcription factor regulons for exploring context-specific gene regulation programs

Regulation of PD-L1 Expression by YY1 in Cancer: Therapeutic Efficacy of Targeting YY1

Novel RNA m⁶A methyltransferase METTL16 inhibitors

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HDAC1/3-dependent moderate liquid–liquid phase separation of YY1 promotes METTL3 expression and AML cell proliferation

Cited by 14 publications

References 57 publications

Specifying cellular context of transcription factor regulons for exploring context-specific gene regulation programs

Specifying cellular context of transcription factor regulons for exploring context-specific gene regulation programs

Regulation of PD-L1 Expression by YY1 in Cancer: Therapeutic Efficacy of Targeting YY1

Novel RNA m6A methyltransferase METTL16 inhibitors

Contact Info

Product

Resources

About

Novel RNA m⁶A methyltransferase METTL16 inhibitors