CDK7-Dependent Transcriptional Addiction in Triple-Negative Breast Cancer

Wang, Yubao; Zhang, Tinghu; Kwiatkowski, Nicholas; Abraham, Brian J.; Lee, Tong Ihn; Xie, Shusen; Yuzugullu, Haluk; Von, Thanh; Li, Heyuan; Lin, Ziao; Stover, Daniel G.; Lim, Elgene; Wang, Zhigang C.; Iglehart, J. Dirk; Young, Richard A.; Gray, Nathanael S.; Zhao, Jean J.

doi:10.1016/j.cell.2015.08.063

Cited by 359 publications

(447 citation statements)

References 70 publications

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“…Recent studies showed that THZ1 potently suppressed cell proliferation and tumour growth in four different types of malignancies through inactivation of RNA polymerase II (RNAPII)-mediated transcription initiation and elongation, including small cell lung cancer,12 neuroblastoma,14 T cell acute lymphoblastic leukaemia16 and triple negative breast cancer 25. To evaluate the antineoplastic properties of THZ1 against OSCC cells, we first performed cell cycle analysis and observed G2/M phase arrest upon THZ1 treatment (see online supplementary figure S4).…”

Section: Resultsmentioning

confidence: 99%

“…We were initially intrigued by the observations that inhibition of general gene transcription by low-dose THZ1 produced much less cytotoxicity in healthy tissues than in OSCC xenograft (see online supplementary figure S5). Recent investigations found that partial transcription inhibition resulted in selective rather than global suppression of those transcripts which were highly dependent on continuous transcription in several types of THZ1-sensitive tumours, but not unresponsive cancers nor non-malignant cells 12 14 16 25. We reasoned that the exceptional sensitivity of several OSCC cells to low-dose THZ1 treatment might be conferred by a set of oncogenes which were extremely addicted to transcriptional activation and were thus particularly vulnerable to CDK7 inhibition.…”

Section: Discussionmentioning

confidence: 97%

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Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma

Jiang

Lin

Mayakonda

et al. 2016

Gut

171

194

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Objectives Oesophageal squamous cell carcinoma (OSCC) is an aggressive malignancy and the major histological subtype of oesophageal cancer. Although recent large-scale genomic analysis has improved the description of the genetic abnormalities of OSCC, few targetable genomic lesions have been identified, and no molecular therapy is available. This study aims to identify druggable candidates in this tumour. Design High-throughput small-molecule inhibitor screening was performed to identify potent anti-OSCC compounds. Whole-transcriptome sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) were conducted to decipher the mechanisms of action of CDK7 inhibition in OSCC. A variety of in vitro and in vivo cellular assays were performed to determine the effects of candidate genes on OSCC malignant phenotypes. Results The unbiased high-throughput small-molecule inhibitor screening led us to discover a highly potent anti-OSCC compound, THZ1, a specific CDK7 inhibitor. RNA-Seq revealed that low-dose THZ1 treatment caused selective inhibition of a number of oncogenic transcripts. Notably, further characterisation of the genomic features of these THZ1-sensitive transcripts demonstrated that they were frequently associated with super-enhancer (SE). Moreover, SE analysis alone uncovered many OSCC lineage-specific master regulators. Finally, integrative analysis of both THZ1-sensitive and SE-associated transcripts identified a number of novel OSCC oncogenes, including PAK4, RUNX1, DNAJB1, SREBF2 and YAP1, with PAK4 being a potential druggable kinase. Conclusions Our integrative approaches led to a catalogue of SE-associated master regulators and oncogenic transcripts, which may significantly promote both the understanding of OSCC biology and the development of more innovative therapies.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma

Jiang

Lin

Mayakonda

et al. 2016

Gut

171

194

View full text Add to dashboard Cite

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“…Given the potent sequence-specific inhibition by polyamide interference, and the demonstrated antitumor activity in xenografts with low host toxicity, it would be very attractive to consider whether there is a role in cancer therapy for these molecules. Transcription inhibition has been explored as a therapeutic strategy in cancer treatment (46)(47)(48)(49). Inhibition of a ubiquitous and essential pathway in cancer could overcome, in part, the drug resistance conferred through the genetic heterogeneity of the disease.…”

Section: Resultsmentioning

confidence: 99%

RNA polymerase II senses obstruction in the DNA minor groove via a conserved sensor motif

Xu¹,

Wang²,

Gotte³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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RNA polymerase II (pol II) encounters numerous barriers during transcription elongation, including DNA strand breaks, DNA lesions, and nucleosomes. Pyrrole-imidazole (Py-Im) polyamides bind to the minor groove of DNA with programmable sequence specificity and high affinity. Previous studies suggest that Py-Im polyamides can prevent transcription factor binding, as well as interfere with pol II transcription elongation. However, the mechanism of pol II inhibition by Py-Im polyamides is unclear. Here we investigate the mechanism of how these minor-groove binders affect pol II transcription elongation. In the presence of site-specifically bound Py-Im polyamides, we find that the pol II elongation complex becomes arrested immediately upstream of the targeted DNA sequence, and is not rescued by transcription factor IIS, which is in contrast to pol II blockage by a nucleosome barrier. Further analysis reveals that two conserved pol II residues in the Switch 1 region contribute to pol II stalling. Our study suggests this motif in pol II can sense the structural changes of the DNA minor groove and can be considered a "minor groove sensor." Prolonged interference of transcription elongation by sequence-specific minor groove binders may present opportunities to target transcription addiction for cancer therapy.Py-Im polyamide | transcription inhibition | minor groove | DNA I n eukaryotes, precursor mRNA synthesis is catalyzed by the RNA polymerase II holoenzyme (pol II), which frequently pauses during transcription elongation (1-3). In addition to regulatory factors that control pol II processivity, various obstacles encountered by pol II can also lead to stalling, and even backtracking, on the DNA template (4). Factors that affect pol II transcription elongation dynamics include intrinsic DNA sequences or structures (5, 6), endogenous epigenetic DNA modifications (7), embedded ribonucleotides (8), DNA lesions (9, 10), small-molecule DNA-binders (11, 12), DNA-binding proteins including nucleosomes (13), and even pol II itself (14, 15). Transient transcriptional pausing or short-lived transcriptional blockage can be rescued by the recruitment of transcription factor IIS (TFIIS) (16, 17), a transcription factor that facilitates the cleavage of backtracked transcript. In contrast, prolonged transcriptional arrest by some bulky DNA lesions triggers either ubiquitination and degradation of pol II, or transcription-coupled nucleotide excision repair, a special DNA repair pathway that preferentially repairs DNA lesions in the transcribed strand (17, 18). Structural, genetic, and biochemical studies have greatly advanced our understanding of how pol II copes with different kinds of covalent DNA lesions caused by oxidation (19, 20), alkylation (21-24), and photocyclo-addition (10). Less well understood are the interactions of the pol II machinery when confronted with a steric blockade by small molecules bound noncovalently in the minor groove of DNA (25-27).Pyrrole-imidazole (Py-Im) polyamides are a class of small molecules that c...

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“…Undoubtedly, applications for treating cancers without BRCA1/2 mutations will also be found, since PARPs intersect with many different cellular stress and genome integrity pathways. Furthermore, given the important role of nuclear PARPs in gene regulation, PARPis may be useful in targeting transcriptionally addicted cancers (Franco and Kraus 2015;Wang et al 2015).…”

Section: From the Bench To The Clinic: Advances In Parp-related Theramentioning

confidence: 99%

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

2017

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The discovery of poly(ADP-ribose) >50 years ago opened a new field, leading the way for the discovery of the poly(ADP-ribose) polymerase (PARP) family of enzymes and the ADP-ribosylation reactions that they catalyze. Although the field was initially focused primarily on the biochemistry and molecular biology of PARP-1 in DNA damage detection and repair, the mechanistic and functional understanding of the role of PARPs in different biological processes has grown considerably of late. This has been accompanied by a shift of focus from enzymology to a search for substrates as well as the first attempts to determine the functional consequences of site-specific ADP-ribosylation on those substrates. Supporting these advances is a host of methodological approaches from chemical biology, proteomics, genomics, cell biology, and genetics that have propelled new discoveries in the field. New findings on the diverse roles of PARPs in chromatin regulation, transcription, RNA biology, and DNA repair have been complemented by recent advances that link ADP-ribosylation to stress responses, metabolism, viral infections, and cancer. These studies have begun to reveal the promising ways in which PARPs may be targeted therapeutically for the treatment of disease. In this review, we discuss these topics and relate them to the future directions of the field.ADP-ribosylation is a reversible post-translational modification (PTM) of proteins resulting in the covalent attachment of a single ADP-ribose unit [i.e., mono(ADP-ribose) (MAR)] or polymers of ADP-ribose units [i.e., poly(ADP-ribose) (PAR)] on a variety of amino acid residues on target proteins (Gibson and Kraus 2012;Daniels et al. 2015a). This modification is mediated by a diverse group of ADPribosyl transferase (ADPRT) enzymes that use ADP-ribose units derived from β-NAD + to catalyze the ADP-ribosylation reaction. These enzymes include bacterial ADPRTs (e.g., cholera toxin and diphtheria toxin) as well as members of three different protein families in yeast and animals: (1) arginine-specific ecto-enzymes (ARTCs), (2) sirtuins, and (3) PAR polymerases (PARPs) . Surprisingly, a recent study showed that the bacterial toxin DarTG can ADP-ribosylate DNA . How this fits into the broader picture of cellular ADP-ribosylation has yet to be determined.In this review, we focus on the mono(ADP-ribosyl)ation (MARylation) and poly(ADP-ribosyl)ation (PARylation) of glutamate, aspartate, and lysine residues by PARP family members. While many reviews have been written on PARPs in the past decade, we highlight the current trends and ideas in the field, in particular those discoveries that have been published in the past 2-3 years.

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CDK7-Dependent Transcriptional Addiction in Triple-Negative Breast Cancer

Cited by 359 publications

References 70 publications

Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma

Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma

RNA polymerase II senses obstruction in the DNA minor groove via a conserved sensor motif

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

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