Notch Represses Transcription by PRC2 Recruitment to the Ternary Complex

Han, Xiaoqing; Ranganathan, Prathibha; Tzimas, Christos; Weaver, Kelly L.; Jin, Ke; Astudillo, Luisana; Zhou, Wen; Zhu, Xiaoxia; Li, Bin; Robbins, David J.; Capobianco, Anthony J.

doi:10.1158/1541-7786.mcr-17-0241

Cited by 16 publications

(14 citation statements)

References 51 publications

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“…Upon activation through cell-to-cell interaction, the Notch intracellular domain is released from the cell membrane and translocates to the nucleus, where it initiates the formation of a ternary complex with Maml and CSL (3,4). It is thought that this ternary complex serves as a scaffold to recruit additional transcriptional coactivators to drive a Notch-dependent transcriptional cascade (5)(6)(7)(8). Therefore, deregulation of Notch leads to the aberrant enforcement of a transcriptional profile that drives a neoplastic program (3,4,9,10).…”

Section: Introductionmentioning

confidence: 99%

Acetylation of Mastermind-like 1 by p300 Drives the Recruitment of NACK to Initiate Notch-Dependent Transcription

et al. 2017

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Although it has long been appreciated that p300 acts as a critical Notch coactivator, the mechanistic details of p300 in Notch-mediated transcription remain unclear. We previously demonstrated that PEAK1-related kinase activating pseudokinase 1 (NACK), also known as SGK223, is a critical coactivator of Notch signaling and binds to the Notch1 ternary complex. Herein we report that p300 and CBP acetylate Mastermind-like 1 (Maml1) on amino acid residues K188 and K189 to recruit NACK to the Notch1 ternary complex, which results in the recruitment of RNA polymerase II to initiate transcription. NACK is recruited to the ternary complexes containing Maml1 and Maml3, but not Maml2. Simultaneous inhibition of p300/ CBP and Notch has a synergistic effect in esophageal adenocarcinoma. In summary, this study provides a deeper mechanistic understanding of the assembly of the Notch transcriptional complex and provides rationale and proof of concept for a combinatorial therapeutic attack on Notch-dependent cancers. Cancer Res; 77(16); 4228-37. Ó2017 AACR.

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Section: Introductionmentioning

confidence: 99%

Acetylation of Mastermind-like 1 by p300 Drives the Recruitment of NACK to Initiate Notch-Dependent Transcription

et al. 2017

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“…Collectively, we brought insight into how the NOTCH1-HES1 pathway was regulated by miR-137. LSD1 has been linked to the repression of NOTCH1 pathway in various cell types [45,[59][60][61][62][63], though one study states that it functions as a corepressor when associated with RBPJ-repressor complex and as a NOTCH1 coactivator upon NOTCH activation [64]. Nevertheless, few studies have reported the interplay between NOTCH1 and LSD1 during the osteogenesis of hASCs and whether this interaction contributes to the osteogenic regulation of miR-137 is still unknown.…”

Section: Discussionmentioning

confidence: 99%

A NOTCH1/LSD1/BMP2 Co-Regulatory Network Mediated by miR-137 Negatively Regulates Osteogenesis of Human Adipose-Derived Stem Cells

Fan

Wang

et al. 2020

Preprint

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Background: MicroRNAs have been recognized as critical regulators for the osteoblastic lineage differentiation of human adipose-derived stem cells (hASCs). Previously, we have displayed that silencing of miR-137 enhances the osteoblastic differentiation potential of hASCs partly through the coordination of lysine-specific histone demethylase 1 (LSD1), bone morphogenetic protein 2 (BMP2), and mothers against decapentaplegic homolog 4 (SMAD4). However, still numerous molecules involved in the osteogenic regulation of miR-137 remain unknown. This study aimed to further elucidate the epigenetic mechanisms of miR-137 on the osteogenic differentiation of hASCs.Methods: hASCs transfected with miR-137 overexpression or knockdown lentiviruses were used to assess the osteogenic capacity by testing the alkaline phosphatase activity, matrix mineralization degree, relative expression level of osteogenesis-associated genes and ectopic osteogenesis in nude mice. Dual-luciferase reporter assay was performed to examine the targeting of the 3' untranslated region (3' UTR) of NOTCH1 by miR-137. Interrelationships of signaling pathways of NOTCH1-hairy and enhancer of split 1 (HES1), LSD1, and BMP2-SMAD4 were thoroughly investigated by separate knockdown of NOTCH1, LSD1, and BMP2.Results: We confirmed that miR-137 directly targeted the 3' UTR of NOTCH1 while positively regulated HES1. After knocking down NOTCH1 or BMP2 individually, we found that these two signals formed a positive feedback loop and activated LSD1. In addition, LSD1 knockdown induced the expression of NOTCH1 while suppressed HES1.Conclusions: Collectively, we proposed a NOTCH1/LSD1/BMP2 co-regulatory signaling network to elucidate the modulation of miR-137 on the osteoblastic differentiation of hASCs, thus providing mechanism-based rationale for miRNA-targeted therapy of bone defect.

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“…Han lymphomas, and along with the ternary complex forms a stable transcriptional repressor complex. This leads to enrichment of H3K27me3 repression and loss of H3K4me3 activation, contributing to downstream repressive epigenetic changes [133]. In addition, preliminary data showed that Notch activation led to direct EZH2 and SUZ12 transcriptional induction, although no evidence has shown that they are direct Notch-target genes [133].…”

Section: Prc2 Loss and Notch Signalingmentioning

confidence: 99%

“…This leads to enrichment of H3K27me3 repression and loss of H3K4me3 activation, contributing to downstream repressive epigenetic changes [133]. In addition, preliminary data showed that Notch activation led to direct EZH2 and SUZ12 transcriptional induction, although no evidence has shown that they are direct Notch-target genes [133]. Intriguingly, there is also interplay between RAS signaling and Notch signaling; in this manner, Notch signaling seems to be downstream of oncogenic RAS, and wildtype Notch1 is needed for oncogenic RAS-mediated neoplastic transformation of human cells in vitro and in vivo [134].…”

Section: Prc2 Loss and Notch Signalingmentioning

confidence: 99%

The Role of Polycomb Repressive Complex in Malignant Peripheral Nerve Sheath Tumor

Zhang

Murray

et al. 2020

Genes

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Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas that can arise most frequently in patients with neurofibromatosis type 1 (NF1). Despite an increasing understanding of the molecular mechanisms that underlie these tumors, there remains limited therapeutic options for this aggressive disease. One potentially critical finding is that a significant proportion of MPNSTs exhibit recurrent mutations in the genes EED or SUZ12, which are key components of the polycomb repressive complex 2 (PRC2). Tumors harboring these genetic lesions lose the marker of transcriptional repression, trimethylation of lysine residue 27 on histone H3 (H3K27me3) and have dysregulated oncogenic signaling. Given the recurrence of PRC2 alterations, intensive research efforts are now underway with a focus on detailing the epigenetic and transcriptomic consequences of PRC2 loss as well as development of novel therapeutic strategies for targeting these lesions. In this review article, we will summarize the recent findings of PRC2 in MPNST tumorigenesis, including highlighting the functions of PRC2 in normal Schwann cell development and nerve injury repair, as well as provide commentary on the potential therapeutic vulnerabilities of a PRC2 deficient tumor cell.

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Notch Represses Transcription by PRC2 Recruitment to the Ternary Complex

Cited by 16 publications

References 51 publications

Acetylation of Mastermind-like 1 by p300 Drives the Recruitment of NACK to Initiate Notch-Dependent Transcription

Acetylation of Mastermind-like 1 by p300 Drives the Recruitment of NACK to Initiate Notch-Dependent Transcription

A NOTCH1/LSD1/BMP2 Co-Regulatory Network Mediated by miR-137 Negatively Regulates Osteogenesis of Human Adipose-Derived Stem Cells

The Role of Polycomb Repressive Complex in Malignant Peripheral Nerve Sheath Tumor

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