Transcriptional Addiction in Cancer

Bradner, James E.; Hnisz, Denes; Young, Richard A.

doi:10.1016/j.cell.2016.12.013

Cited by 963 publications

(1,005 citation statements)

References 140 publications

(196 reference statements)

Supporting

Mentioning

986

Contrasting

Unclassified

Order By: Relevance

“…Super-enhancers (SEs) regulate genes with prominent roles in healthy and diseased cellular states (14, 15, 19–25, 49, 50). SEs and their components have been proposed to form phase-separated condensates (30), but with no direct evidence.…”

Section: Discussionmentioning

confidence: 99%

Coactivator condensation at super-enhancers links phase separation and gene control

Sabari

Dall’Agnese

Boija

et al. 2018

Science

Self Cite

1,994

111

1,868

View full text Add to dashboard Cite

Super-enhancers (SEs) are clusters of enhancers that cooperatively assemble a high density of transcriptional apparatus to drive robust expression of genes with prominent roles in cell identity. Here, we demonstrate that the SE-enriched transcriptional coactivators BRD4 and MED1 form nuclear puncta at SEs that exhibit properties of liquid-like condensates and are disrupted by chemicals that perturb condensates. The intrinsically disordered regions (IDRs) of BRD4 and MED1 can form phase-separated droplets and MED1-IDR droplets can compartmentalize and concentrate transcription apparatus from nuclear extracts. These results support the idea that coactivators form phase-separated condensates at SEs that compartmentalize and concentrate the transcription apparatus, suggest a role for coactivator IDRs in this process, and offer insights into mechanisms involved in control of key cell identity genes.

show abstract

Section: Discussionmentioning

confidence: 99%

Coactivator condensation at super-enhancers links phase separation and gene control

Sabari

Dall’Agnese

Boija

et al. 2018

Science

Self Cite

1,994

111

1,868

View full text Add to dashboard Cite

show abstract

“…Virtually all of the discovered super enhancers were bound by 3 or 4 of these MTFs, and associated with the highest levels of gene expression. Remarkably, the presence of MYCN at these hyperactive regions resembles the function of MYC as a general transcriptional amplifier (29) and may underlie transcriptional addiction in FP-RMS (40). Together, these four MTFs cause a profound epigenetic reprogramming, freezing the cells in a myoblastic state with PAX3-FOXO1 as the conductor.…”

Section: Discussionmentioning

confidence: 99%

PAX3–FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability

et al. 2017

View full text Add to dashboard Cite

Alveolar rhabdomyosarcoma is a life-threatening myogenic cancer of children and adolescent young adults, driven primarily by the chimeric transcription factor PAX3-FOXO1. The mechanisms by which PAX3-FOXO1 dysregulates chromatin are unknown. We fi nd PAX3-FOXO1 reprograms the cis -regulatory landscape by inducing de novo super enhancers. PAX3-FOXO1 uses super enhancers to set up autoregulatory loops in collaboration with the master transcription factors MYOG, MYOD, and MYCN. This myogenic super enhancer circuitry is consistent across cell lines and primary tumors. Cells harboring the fusion gene are selectively sensitive to small-molecule inhibition of protein targets induced by, or bound to, PAX3-FOXO1-occupied super enhancers. Furthermore, PAX3-FOXO1 recruits and requires the BET bromodomain protein BRD4 to function at super enhancers, resulting in a complete dependence on BRD4 and a signifi cant susceptibility to BRD inhibition. These results yield insights into the epigenetic functions of PAX3-FOXO1 and reveal a specifi c vulnerability that can be exploited for precision therapy.SIGNIFICANCE: PAX3-FOXO1 drives pediatric fusion-positive rhabdomyosarcoma, and its chromatinlevel functions are critical to understanding its oncogenic activity. We fi nd that PAX3-FOXO1 establishes a myoblastic super enhancer landscape and creates a profound subtype-unique dependence on BET bromodomains, the inhibition of which ablates PAX3-FOXO1 function, providing a mechanistic rationale for exploring BET inhibitors for patients bearing PAX-fusion rhabdomyosarcoma. Cancer Discov; 7(8);

show abstract

“…The hallmarks of cancer cells -sustained proliferation, replicative immortality, apoptotic evasion and metastasis — are supported by aberrant gene expression programs [1, 2]. Thus, not surprisingly, transcriptional deregulation driven by changes in the genetic and epigenetic landscape is a fundamental mechanism of cancer [3, 4]. The intimate relationship between transcriptional deregulation and oncogenesis is underscored by the observation that many oncogenes and tumor suppressor genes encode TFs, strongly implicating altered gene regulation as a key oncogenic mechanism [1–4].…”

Section: Transcriptional Deregulation In Cancermentioning

confidence: 99%

Super-Enhancer-Driven Transcriptional Dependencies in Cancer

2017

View full text Add to dashboard Cite

Transcriptional deregulation is one of the core tenets of cancer biology and is underpinned by alterations in both protein-coding genes and noncoding regulatory elements. Large regulatory elements, so-called super-enhancers (SEs), are central to the maintenance of cancer cell identity, and promote oncogenic transcription to which cancer cells become highly addicted. Such dependence on SE-driven transcription for proliferation and survival offers an Achilles’ heel for the therapeutic targeting of cancer cells. Indeed, inhibition of the cellular machinery required for the assembly and maintenance of SEs dampens oncogenic transcription and inhibits tumor growth. In this article, we review the organization, function, and regulation of oncogenic SEs and their contribution to the cancer cell state.

show abstract

Transcriptional Addiction in Cancer

Cited by 963 publications

References 140 publications

Coactivator condensation at super-enhancers links phase separation and gene control

Coactivator condensation at super-enhancers links phase separation and gene control

PAX3–FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability

Super-Enhancer-Driven Transcriptional Dependencies in Cancer

Contact Info

Product

Resources

About