Unraveling cell death mysteries

a

Transcriptional activation

b

© 2016 Nature America, Inc. All rights reserved.

Figure 1 | Modulation of BET bromodomain functional activity. (a) The BET bromodomain protein BRD4 binds acetylated lysines present on histones to initiate transcription through recruitment of pTEFb,

which phosphorylates and activates RNA polymerase II (RNA PolII). (b) Inhibition of the binding of the protein TAF1 with a small molecule targeting its bromodomain site blocks BRD4-mediated transcription, indicating an essential crosstalk between the bromodomain proteins.

(Fig. 1b). Counterscreening of CeMMEC1 across a panel of bromodomain-containing proteins indicated that the compound had affinity for BRD9, CREBBP, EP300 and TAF1; however, only TAF1 knockdown phenocopied the effects of the compound. Further, TAF1 was shown through

co-immunoprecipitation experiments to interact directly with BRD4, and knockdown of TAF1 sensitized cancer cells to BRD4 inhibition. A small structure–activity

relationship program, informed by studies of the docking of CeMMEC1 into TAF1, led to the identification of more selective TAF1 inhibitors, which in turn were

shown in a cell viability assay to synergize with JQ-1.

The data presented in this paper clearly indicate that TAF1 interacts directly with BRD4 and is centrally involved in modulating its functional activity; this function, combined with TAF1’s roles in cell cycle control, p53 degradation and MYC transcriptional activation, supports the

development of selective TAF1 inhibitors for the treatment of cancers. To date, however, there are few reports describing selective TAF1 inhibitors despite the bromodomain of TAF1 being classified as druggable7. The molecule CeMMEC1 and analogs represent a promising starting point for such drug-discovery programs. The type of phenotypic screen employed in this work, which involves derepression of a silenced fluorescent reporter, has been disclosed previously in other screens involving epigenetic protein targets8,9. As with these earlier reports, the work here clearly demonstrates the power of this screening strategy to interrogate epigenetic processes and identify biologically active small molecules in an unbiased manner.

The identification of CeMMEC1 as a TAF1 inhibitor that can modulate the functional activity of BRD4 has contributed to our understanding of this transcriptionally important protein and at the same time

helped validate a promising new drug target. It will be interesting to determine whether TAF1 also associates with other members of the BET bromodomain family. If not, inhibition of TAF1 binding may allow

selective modulation of BRD4 activity, which in turn may offer the possibility of obtaining the therapeutic benefit of BRD4 inhibition without the side effects of the clinically

trialled pan-BET inhibitors. At present, only the recently described PROTAC (proteolysis-targeted chimera) molecules reported by Ciulli and co-workers selectively target BRD4 (ref. 10). In addition, understanding the differential transcriptional effects of TAF1 as compared to BET inhibition may also reveal alternative therapeutic opportunities for TAF1 inhibitors. ■

Christopher J. Burns is in The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. e-mail: burns@wehi.edu.auReferences

1. Filippakopoulos, P. & Knapp, S. Nat. Rev. Drug Discov. 13, 337–356 (2014).

2. Sdelci, S. et al. Nat. Chem. Biol. 12, 504–510 (2016).3. Lovén, J. et al. Cell 153, 320–334 (2013).

4. Liu, X., Vorontchikhina, M., Wang, Y.L., Faiola, F. & Martinez, E. Mol. Cell. Biol. 28, 108–121 (2008).

5. Li, H.-H., Li, A.G., Sheppard, H.M. & Liu, X. Mol. Cell 13, 867–878 (2004).

6. Belkina, A.C. & Denis, G.V. Nat. Rev. Cancer 12, 465–477 (2012).7. Vidler, L.R., Brown, N., Knapp, S. & Hoelder, S. J. Med. Chem. 55, 7346–7359 (2012).

8. Tran, T.A. et al. ACS Chem. Biol. 9, 2603–2611 (2014).9. Wang, L. et al. Nat. Commun. 4, 2035 (2013).

10. Zengerle, M., Chan, K.H. & Ciulli, A. ACS Chem. Biol. 10, 1770–1777 (2015).

pCompeting financial interests

The author declares no competing financial interests.

Unraveling cell death mysteries

Xiomaris M Cotto-Rios & Evripidis Gavathiotis

CHEMICAL GENETICS

Non-apoptotic regulated cell death is not fully characterized, particularly for ferroptosis, the iron- and ROS-dependent form of regulated cell death. A systematic approach using modulatory profiling and cell line sensitivity analysis has unraveled the association of lipid metabolism with ferroptosis and enabled the discovery of a novel specific ferroptosis inducer.

R

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egulated cell death, despite its negative connotation, is essential in many

physiological processes, including tissue sculpting during embryogenesis, development of the immune system and destruction of damaged cells1. The dysregulation of cell death has been associated with many pathological processes, such as cancer,

neurodegeneration and tissue injury. A well-characterized form of regulated cell death is apoptosis; however, alternative mechanisms such as necroptosis2, autophagy3 and ferroptosis4 have been classified but remain less understood. To gain further insight and dissect the mechanisms governing these alternative forms of cell death, Shimada et al.5 embarked on a small-molecule phenotypic screen for inducers of non-apoptotic cell death.

nature chemical biology | VOL 12 | juLy 2016 | http://doc.guandang.net/naturechemicalbiology

Figure 1 | Induction of ferroptosis by FIN56. FIN56 promotes ferroptosis by two distinct mechanisms: (i) negative regulation of GPX4 protein levels and (ii) activation of squalene synthase (SQS), which acts .

dedownstream of HMG-CoA reductase in the mevalonate pathway. In one mechanism (purple b …… 此处隐藏：10229字，全部文档内容请下载后查看。喜欢就下载吧 ……