Selective gene dependencies in MYCN-amplified neuroblastoma include the core transcriptional regulatory circuitry

Durbin, Adam D.; Zimmerman, Mark W.; Dharia, Neekesh V.; Abraham, Brian J.; Iniguez, Amanda Balboni; Weichert-Leahey, Nina; He, Shuning; Krill-Burger, John M.; Root, David E.; Vázquez, Francisca; Tsherniak, Aviad; Hahn, William C.; Golub, Todd R.; Young, Richard A.; Look, A. Thomas; Stegmaier, Kimberly

doi:10.1038/s41588-018-0191-z

Cited by 210 publications

(331 citation statements)

References 44 publications

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“…We therefore profiled genome-wide distribution of H3K27Ac by ChIP-sequencing of JQ1 naive and resistant cells across both cell line models (Fig S3I-P). In concordance with previous studies, SE-associated genes: HAND1/2, GATA3, and PHOX2B , were identified in naive cells (Boeva et al, 2017; Chipumuro et al, 2014; van Groningen et al, 2017, Durbin et al, 2018). SE-marked genes and typical enhancer (TE)-marked genes, defined by high H3K27Ac signal in enhancer regions, were preferentially repressed by JQ1 (Figure S4A, B).…”

Section: Resultssupporting

confidence: 91%

Resistance to Epigenetic-Targeted Therapy Engenders Tumor Cell Vulnerabilities Associated with Enhancer Remodeling

et al. 2018

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SUMMARY Drug resistance represents a major challenge to achieving durable responses to cancer therapeutics. Resistance mechanisms to epigenetically-targeted drugs remain largely unexplored. We used BET inhibition in neuroblastoma as a prototype to model resistance to chromatin modulatory therapeutics. Genome-scale, pooled lentiviral open reading frame (ORF) and CRISPR knockout rescue screens nominated the PI3K pathway as promoting resistance to BET inhibition. Transcriptomic and chromatin profiling of resistant cells revealed that global enhancer remodeling is associated with upregulation of receptor tyrosine kinases (RTKs), activation of PI3K signaling and vulnerability to RTK/PI3K inhibition. Large-scale combinatorial screening with BET inhibitors identified PI3K inhibitors among the most synergistic upfront combinations. These studies provide a roadmap to elucidate resistance to epigenetic-targeted therapeutics and inform efficacious combination therapies.

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Section: Resultssupporting

confidence: 91%

Resistance to Epigenetic-Targeted Therapy Engenders Tumor Cell Vulnerabilities Associated with Enhancer Remodeling

et al. 2018

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“…Accumulating evidence indicates that tumor cells are driven by a small set of transcription factors (TFs) that control global gene expression programs (Durbin et al, 2018;Mansour et al, 2014;Sanda et al, 2012). While disused in corresponding healthy cells, some tumor-driving master transcription factors (MTFs) are often developmental regulators that are aberrantly expressed and functionally co-opted to regulate tumor cell states.…”

Section: Introductionmentioning

confidence: 99%

“…For example, regulators of T cell development, TAL1, GATA3, RUNX1, and MYB, are over-expressed and coregulate oncogenic programs in T-cell acute lymphoblastic leukemias (Mansour et al, 2014;Sanda et al, 2012). Additionally, developmental regulators MYCN, HAND2, ISL1, PHOX2B, GATA3, and TBX2 have been identified as MTFs in neuroblastoma (Durbin et al, 2018). MTFs are generally expressed in only a limited number of cell types, consistent with their potent role in establishing a gene expression program that drives cell identity (D'Alessio et al, 2015;Whyte et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Although TFs are notoriously difficult to directly target with small molecules, several MTFs have been shown to be highly sensitive to pharmaceutical inhibition of general transcriptional regulators, including those that target bromodomain (BRD)-containing proteins and transcriptional cyclin-dependent kinase 7 (Chapuy et al, 2013;Durbin et al, 2018;Kwiatkowski et al, 2014;Wang et al, 2015). The expression of tumor cell MTFs are often driven by large clusters of enhancers, or termed super-or stretch-enhancers (SEs) (Lovén et al, 2013;Parker et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…MTFs are thought to form core transcriptional regulatory circuitries by co-occupying genomic sites, particularly at SEs, and co-regulating the expression of MTF genes and others genes critical for cellular identity (Chen et al, 2019a;Durbin et al, 2018;Sanda et al, 2012). Presently, the main approaches to identifying MTFs in cancer cells attempts to model these features by identifying TFs predicted to exhibit evidence of interconnected autoregulation Saint-André et al, 2016;Zhang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Predicting master transcription factors from pan-cancer expression data

Reddy

Fonseca

Fuente

et al. 2019

Preprint

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The function of critical developmental regulators can be subverted by cancer cells to control expression of oncogenic transcriptional programs. These "master transcription factors" (MTFs) are often essential for cancer cell survival and represent vulnerabilities that can be exploited therapeutically. The current approaches to identify candidate MTFs examine super-enhancer associated transcription factor-encoding genes with high connectivity in network models. This relies on chromatin immunoprecipitation-sequencing (ChIP-seq) data, which is technically challenging to obtain from primary tumors, and is currently unavailable for many cancer types and clinically relevant subtypes. In contrast, gene expression data are more widely available, especially for rare tumors and subtypes where MTFs have yet to be discovered. We have developed a predictive algorithm called CaCTS (Cancer Core Transcription factor Specificity) to identify candidate MTFs using pancancer RNA-sequencing data from The Cancer Genome Atlas. The algorithm identified 273 candidate MTFs across 34 tumor types and recovered known tumor MTFs. We also made novel predictions, including for cancer types and subtypes for which MTFs have not yet been characterized. Clustering based on MTF predictions reproduced anatomic groupings of tumors that share 1-2 lineage-specific candidates, but also dictated functional groupings, such as a squamous group that comprised five tumor subtypes sharing 3 common MTFs. PAX8, SOX17, and MECOM were candidate factors in high-grade serous ovarian cancer (HGSOC), an aggressive tumor type where the core regulatory circuit is currently uncharacterized. PAX8, SOX17, and MECOM are required for cell viability and lie proximal to super-enhancers in HGSOC cells. ChIPseq revealed that these factors co-occupy HGSOC regulatory elements globally and co-bind at critical gene loci including MUC16 (CA-125). Addiction to these factors was confirmed in studies using THZ1 to inhibit transcription in HGSOC cells, suggesting early down-regulation of these genes may be responsible for cytotoxic effects of THZ1 on HGSOC models. Identification of MTFs across 34 tumor types and 140 subtypes, especially for those with limited understanding of transcriptional drivers paves the way to therapeutic targeting of MTFs in a broad spectrum of cancers.

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CCNB1IP1 prevents ubiquitination‐mediated destabilization of MYCN and potentiates tumourigenesis of MYCN‐amplificated neuroblastoma

Zhou

Yan

Zhou

et al. 2023

Clinical & Translational Med

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Background MYCN amplification as a common genetic alteration that correlates with a poor prognosis for neuroblastoma (NB) patients. However, given the challenge of directly targeting MYCN, indirect strategies to modulate MYCN by interfering with its cofactors are attractive in NB treatment. Although cyclin B1 interacting protein 1 (CCNB1IP1) has been found to be upregulated in MYCN‐driven mouse NB tissues, its regulation with MYCN and collaboration in driving the biological behaviour of NB remains unknown. Methods To evaluate the expression and clinical significance of CCNB1IP1 in NB patients, public datasets, clinical NB samples and cell lines were explored. MTT, EdU incorporation, colony and tumour sphere formation assays, and a mouse xenograft tumour model were utilized to examine the biological function of CCNB1IP1. The reciprocal manipulation of CCNB1IP1 and MYCN and the underlying mechanisms involved were investigated by gain‐ and loss‐of‐function approaches, dual‐luciferase assay, chromatin immunoprecipitation (CHIP) and co‐immunoprecipitation (Co‐IP) experiments. Results CCNB1IP1 was upregulated in MYCN‐amplified (MYCN‐AM) NB cell lines and patients‐derived tumour tissues, which was associated with poor prognosis. Phenotypic studies revealed that CCNB1IP1 facilitated the proliferation and tumourigenicity of NB cells in cooperation with MYCN in vitro and in vivo. Mechanistically, MYCN directly mediates the transcription of CCNB1IP1, which in turn attenuated the ubiquitination and degradation of MYCN protein, thus enhancing CCNB1IP1‐MYCN cooperativity. Moreover, CCNB1IP1 competed with F box/WD‐40 domain protein 7 (FBXW7) for MYCN binding and enabled MYCN‐mediated tumourigenesis in a C‐terminal domain‐dependent manner. Conclusions Our study revealed a previously uncharacterized mechanism of CCNB1IP1‐mediated MYCN protein stability and will provide new prospects for precise treatment of MYCN‐AM NB based on MYCN‐CCNB1IP1 interaction.

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Selective gene dependencies in MYCN-amplified neuroblastoma include the core transcriptional regulatory circuitry

Cited by 210 publications

References 44 publications

Resistance to Epigenetic-Targeted Therapy Engenders Tumor Cell Vulnerabilities Associated with Enhancer Remodeling

Resistance to Epigenetic-Targeted Therapy Engenders Tumor Cell Vulnerabilities Associated with Enhancer Remodeling

Predicting master transcription factors from pan-cancer expression data

CCNB1IP1 prevents ubiquitination‐mediated destabilization of MYCN and potentiates tumourigenesis of MYCN‐amplificated neuroblastoma

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