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TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma

Seong, Bo Kyung A. ; Dharia, Neekesh V. ; Lin, Shan ; [et al.]

Elsevier BV ; 2021

In: Cancer Cell Vol. 39, No. 9 ( 2021-09), p. 1262-1278.e7

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In: Cancer Cell, Elsevier BV, Vol. 39, No. 9 ( 2021-09), p. 1262-1278.e7

Type of Medium: Online Resource

ISSN: 1535-6108

URL: Article

DOI: 10.1016/j.ccell.2021.07.003

Language: English

Publisher: Elsevier BV

Publication Date: 2021

detail.hit.zdb_id: 2074034-7

detail.hit.zdb_id: 2078448-X

SSG: 12

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Huang, Hai-Tsang ; Seo, Hyuk-Soo ; Zhang, Tinghu ; [et al.]

eLife Sciences Publications, Ltd ; 2017

In: eLife Vol. 6 ( 2017-09-19)

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In: eLife, eLife Sciences Publications, Ltd, Vol. 6 ( 2017-09-19)

Abstract: Thorough preclinical target validation is essential for the success of drug discovery efforts. In this study, we combined chemical and genetic perturbants, including the development of a novel selective maternal embryonic leucine zipper kinase (MELK) inhibitor HTH-01-091, CRISPR/Cas9-mediated MELK knockout, a novel chemical-induced protein degradation strategy, RNA interference and CRISPR interference to validate MELK as a therapeutic target in basal-like breast cancers (BBC). In common culture conditions, we found that small molecule inhibition, genetic deletion, or acute depletion of MELK did not significantly affect cellular growth. This discrepancy to previous findings illuminated selectivity issues of the widely used MELK inhibitor OTSSP167, and potential off-target effects of MELK-targeting short hairpins. The different genetic and chemical tools developed here allow for the identification and validation of any causal roles MELK may play in cancer biology, which will be required to guide future MELK drug discovery efforts. Furthermore, our study provides a general framework for preclinical target validation.

Type of Medium: Online Resource

ISSN: 2050-084X

URL: Article

DOI: 10.7554/eLife.26693

DOI: 10.7554/eLife.26693.001

DOI: 10.7554/eLife.26693.002

DOI: 10.7554/eLife.26693.004

DOI: 10.7554/eLife.26693.003

DOI: 10.7554/eLife.26693.005

DOI: 10.7554/eLife.26693.006

DOI: 10.7554/eLife.26693.007

DOI: 10.7554/eLife.26693.008

DOI: 10.7554/eLife.26693.009

DOI: 10.7554/eLife.26693.010

DOI: 10.7554/eLife.26693.011

DOI: 10.7554/eLife.26693.014

DOI: 10.7554/eLife.26693.012

DOI: 10.7554/eLife.26693.013

DOI: 10.7554/eLife.26693.015

DOI: 10.7554/eLife.26693.019

DOI: 10.7554/eLife.26693.020

DOI: 10.7554/eLife.26693.016

DOI: 10.7554/eLife.26693.017

DOI: 10.7554/eLife.26693.018

DOI: 10.7554/eLife.26693.021

DOI: 10.7554/eLife.26693.022

DOI: 10.7554/eLife.26693.023

DOI: 10.7554/eLife.26693.024

DOI: 10.7554/eLife.26693.025

DOI: 10.7554/eLife.26693.026

DOI: 10.7554/eLife.26693.027

DOI: 10.7554/eLife.26693.028

DOI: 10.7554/eLife.26693.029

DOI: 10.7554/eLife.26693.030

DOI: 10.7554/eLife.26693.031

DOI: 10.7554/eLife.26693.032

DOI: 10.7554/eLife.26693.033

DOI: 10.7554/eLife.26693.034

DOI: 10.7554/eLife.26693.035

DOI: 10.7554/eLife.26693.036

DOI: 10.7554/eLife.26693.037

DOI: 10.7554/eLife.26693.042

DOI: 10.7554/eLife.26693.043

Language: English

Publisher: eLife Sciences Publications, Ltd

Publication Date: 2017

detail.hit.zdb_id: 2687154-3

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Zeng, Mei ; Kwiatkowski, Nicholas P ; Zhang, Tinghu ; [et al.]

eLife Sciences Publications, Ltd ; 2018

In: eLife Vol. 7 ( 2018-11-13)

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In: eLife, eLife Sciences Publications, Ltd, Vol. 7 ( 2018-11-13)

Abstract: High-grade serous ovarian cancer is characterized by extensive copy number alterations, among which the amplification of MYC oncogene occurs in nearly half of tumors. We demonstrate that ovarian cancer cells highly depend on MYC for maintaining their oncogenic growth, indicating MYC as a therapeutic target for this difficult-to-treat malignancy. However, targeting MYC directly has proven difficult. We screen small molecules targeting transcriptional and epigenetic regulation, and find that THZ1 - a chemical inhibiting CDK7, CDK12, and CDK13 - markedly downregulates MYC. Notably, abolishing MYC expression cannot be achieved by targeting CDK7 alone, but requires the combined inhibition of CDK7, CDK12, and CDK13. In 11 patient-derived xenografts models derived from heavily pre-treated ovarian cancer patients, administration of THZ1 induces significant tumor growth inhibition with concurrent abrogation of MYC expression. Our study indicates that targeting these transcriptional CDKs with agents such as THZ1 may be an effective approach for MYC-dependent ovarian malignancies.

Type of Medium: Online Resource

ISSN: 2050-084X

URL: Article

DOI: 10.7554/eLife.39030

DOI: 10.7554/eLife.39030.001

DOI: 10.7554/eLife.39030.002

DOI: 10.7554/eLife.39030.003

DOI: 10.7554/eLife.39030.004

DOI: 10.7554/eLife.39030.005

DOI: 10.7554/eLife.39030.006

DOI: 10.7554/eLife.39030.007

DOI: 10.7554/eLife.39030.008

DOI: 10.7554/eLife.39030.009

DOI: 10.7554/eLife.39030.010

DOI: 10.7554/eLife.39030.011

DOI: 10.7554/eLife.39030.012

DOI: 10.7554/eLife.39030.013

DOI: 10.7554/eLife.39030.014

DOI: 10.7554/eLife.39030.016

DOI: 10.7554/eLife.39030.017

DOI: 10.7554/eLife.39030.018

DOI: 10.7554/eLife.39030.022

DOI: 10.7554/eLife.39030.023

Language: English

Publisher: eLife Sciences Publications, Ltd

Publication Date: 2018

detail.hit.zdb_id: 2687154-3

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Identification of a potent and selective covalent Pin1 inhibitor

Pinch, Benika J. ; Doctor, Zainab M. ; Nabet, Behnam ; [et al.]

Springer Science and Business Media LLC ; 2020

In: Nature Chemical Biology Vol. 16, No. 9 ( 2020-09), p. 979-987

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In: Nature Chemical Biology, Springer Science and Business Media LLC, Vol. 16, No. 9 ( 2020-09), p. 979-987

Type of Medium: Online Resource

ISSN: 1552-4450 , 1552-4469

URL: Article

DOI: 10.1038/s41589-020-0550-9

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 2190276-8

SSG: 12

SSG: 15,3

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Structure-Based Design of YShaped Covalent TEAD Inhibitors

Lu, Wenchao ; Fan, Mengyang ; Ji, Wenzhi ; [et al.]

American Chemical Society (ACS) ; 2023

In: Journal of Medicinal Chemistry Vol. 66, No. 7 ( 2023-04-13), p. 4617-4632

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In: Journal of Medicinal Chemistry, American Chemical Society (ACS), Vol. 66, No. 7 ( 2023-04-13), p. 4617-4632

Type of Medium: Online Resource

ISSN: 0022-2623 , 1520-4804

URL: Article

DOI: 10.1021/acs.jmedchem.2c01548

DOI: 10.1021/acs.jmedchem.2c01548.s001

DOI: 10.1021/acs.jmedchem.2c01548.s002

Language: English

Publisher: American Chemical Society (ACS)

Publication Date: 2023

detail.hit.zdb_id: 1491411-6

SSG: 15,3

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Transcription control by the ENL YEATS domain in acute leukaemia

Erb, Michael A. ; Scott, Thomas G. ; Li, Bin E. ; [et al.]

Springer Science and Business Media LLC ; 2017

In: Nature Vol. 543, No. 7644 ( 2017-03-09), p. 270-274

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In: Nature, Springer Science and Business Media LLC, Vol. 543, No. 7644 ( 2017-03-09), p. 270-274

Type of Medium: Online Resource

ISSN: 0028-0836 , 1476-4687

URL: Article

DOI: 10.1038/nature21688

RVK:

TA 1000

RVK:

UA 1000

RVK:

WA 15000

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2017

detail.hit.zdb_id: 120714-3

detail.hit.zdb_id: 1413423-8

SSG: 11

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Polypharmacology-based kinome screen identifies new regulators of KSHV reactivation

Olson, Annabel T. ; Kang, Yuqi ; Ladha, Anushka M. ; [et al.]

Public Library of Science (PLoS) ; 2023

In: PLOS Pathogens Vol. 19, No. 9 ( 2023-9-5), p. e1011169-

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In: PLOS Pathogens, Public Library of Science (PLoS), Vol. 19, No. 9 ( 2023-9-5), p. e1011169-

Abstract: Kaposi’s sarcoma-associated herpesvirus (KSHV) causes several human diseases including Kaposi’s sarcoma (KS), a leading cause of cancer in Africa and in patients with AIDS. KS tumor cells harbor KSHV predominantly in a latent form, while typically 〈 5% contain lytic replicating virus. Because both latent and lytic stages likely contribute to cancer initiation and progression, continued dissection of host regulators of this biological switch will provide insights into fundamental pathways controlling the KSHV life cycle and related disease pathogenesis. Several cellular protein kinases have been reported to promote or restrict KSHV reactivation, but our knowledge of these signaling mediators and pathways is incomplete. We employed a polypharmacology-based kinome screen to identify specific kinases that regulate KSHV reactivation. Those identified by the screen and validated by knockdown experiments included several kinases that enhance lytic reactivation: ERBB2 (HER2 or neu ), ERBB3 (HER3), ERBB4 (HER4), MKNK2 (MNK2), ITK, TEC, and DSTYK (RIPK5). Conversely, ERBB1 (EGFR1 or HER1), MKNK1 (MNK1) and FRK (PTK5) were found to promote the maintenance of latency. Mechanistic characterization of ERBB2 pro-lytic functions revealed a signaling connection between ERBB2 and the activation of CREB1, a transcription factor that drives KSHV lytic gene expression. These studies provided a proof-of-principle application of a polypharmacology-based kinome screen for the study of KSHV reactivation and enabled the discovery of both kinase inhibitors and specific kinases that regulate the KSHV latent-to-lytic replication switch.

Type of Medium: Online Resource

ISSN: 1553-7374

URL: Article

DOI: 10.1371/journal.ppat.1011169

DOI: 10.1371/journal.ppat.1011169.g001

DOI: 10.1371/journal.ppat.1011169.g002

DOI: 10.1371/journal.ppat.1011169.g003

DOI: 10.1371/journal.ppat.1011169.g004

DOI: 10.1371/journal.ppat.1011169.g005

DOI: 10.1371/journal.ppat.1011169.g006

DOI: 10.1371/journal.ppat.1011169.g007

DOI: 10.1371/journal.ppat.1011169.g008

DOI: 10.1371/journal.ppat.1011169.g009

DOI: 10.1371/journal.ppat.1011169.s001

DOI: 10.1371/journal.ppat.1011169.s002

DOI: 10.1371/journal.ppat.1011169.s003

DOI: 10.1371/journal.ppat.1011169.s004

DOI: 10.1371/journal.ppat.1011169.s005

DOI: 10.1371/journal.ppat.1011169.s006

DOI: 10.1371/journal.ppat.1011169.s007

DOI: 10.1371/journal.ppat.1011169.s008

DOI: 10.1371/journal.ppat.1011169.s009

DOI: 10.1371/journal.ppat.1011169.s010

DOI: 10.1371/journal.ppat.1011169.s011

DOI: 10.1371/journal.ppat.1011169.s012

DOI: 10.1371/journal.ppat.1011169.s013

DOI: 10.1371/journal.ppat.1011169.s014

DOI: 10.1371/journal.ppat.1011169.s015

DOI: 10.1371/journal.ppat.1011169.s016

DOI: 10.1371/journal.ppat.1011169.s017

DOI: 10.1371/journal.ppat.1011169.s018

DOI: 10.1371/journal.ppat.1011169.s019

DOI: 10.1371/journal.ppat.1011169.s020

DOI: 10.1371/journal.ppat.1011169.r001

DOI: 10.1371/journal.ppat.1011169.r002

DOI: 10.1371/journal.ppat.1011169.r003

DOI: 10.1371/journal.ppat.1011169.r004

Language: English

Publisher: Public Library of Science (PLoS)

Publication Date: 2023

detail.hit.zdb_id: 2205412-1

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Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells

Mehta, Stuti ; Buyanbat, Altantsetseg ; Kai, Yan ; [et al.]

Elsevier BV ; 2022

In: Cell Chemical Biology Vol. 29, No. 8 ( 2022-08), p. 1273-1287.e8

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In: Cell Chemical Biology, Elsevier BV, Vol. 29, No. 8 ( 2022-08), p. 1273-1287.e8

Type of Medium: Online Resource

ISSN: 2451-9456

URL: Article

DOI: 10.1016/j.chembiol.2022.06.007

Language: English

Publisher: Elsevier BV

Publication Date: 2022

detail.hit.zdb_id: 2850144-5

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Exploring the target scope of KEAP1 E3 ligase-based PROTACs

Du, Guangyan ; Jiang, Jie ; Henning, Nathaniel J. ; [et al.]

Elsevier BV ; 2022

In: Cell Chemical Biology Vol. 29, No. 10 ( 2022-10), p. 1470-1481.e31

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In: Cell Chemical Biology, Elsevier BV, Vol. 29, No. 10 ( 2022-10), p. 1470-1481.e31

Type of Medium: Online Resource

ISSN: 2451-9456

URL: Article

DOI: 10.1016/j.chembiol.2022.08.003

Language: English

Publisher: Elsevier BV

Publication Date: 2022

detail.hit.zdb_id: 2850144-5

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Abstract 740: Investigating the role of epigenetic mechanisms upon aberrant signaling network activation.

Nabet, Behnam ; Braun, Rosemary ; Popovic, Relja ; [et al.]

American Association for Cancer Research (AACR) ; 2013

In: Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 740-740

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In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 740-740

Abstract: Growth factor (GF) stimulation of quiescent cells activates critical receptor tyrosine kinase (RTK) signaling pathways as well as waves of downstream gene expression to drive cell proliferation, survival, and migration. Aberrant activation of RTK signaling networks is a root cause of the uncontrolled cell growth and cell survival seen in cancer. In this study, we aim to uncover the role of epigenetic mechanisms in controlling the dynamic gene expression changes that occur as a cell is activated from a quiescent state, in normal and oncogenic cellular contexts. In order to compare controlled RTK signaling with hyperactive RTK signaling cellular states, we created a cell culture system to modulate the duration and intensity of RTK activation. We genetically deleted the Sprouty (Spry) genes, a family of negative feedback inhibitors of RTK signaling that function as putative tumor suppressors. The Spry deficient cells are hypersensitive to several GFs and show significantly enhanced and prolonged activation of several critical RTK signaling pathways, including the Ras-MAPK pathway. Additionally, the Spry deficient cells possess accelerated cell growth and increased tumorigenic potential compared to their wild-type counterparts. To determine whether this deregulated signaling results in aberrant gene expression, quiescent Spry wild-type and deficient cells were stimulated with GFs, and microarrays were used to profile changes in gene expression over time. Deregulated RTK signaling due to the absence of Spry leads to abnormal expression of a large subset of genes. Specifically, many genes display display not only changes in the level of expression, but aberrant patterns of response to GF stimulation. We determined that genes with deregulated activation in Spry deficient cells display significant differences in histone tail modifications at promoter regions and distal regulatory elements. Interestingly, these changes are evident in the quiescent cellular state as well as upon GF-mediated RTK network activation. Our work suggests that dynamic changes in a cell's epigenetic landscape contribute to the deregulated activation of genes upon hyperactive RTK signaling. Our study will provide a comprehensive view of how epigenetic mechanisms contribute to aberrant gene expression in oncogenic cellular contexts. Citation Format: Behnam Nabet, Rosemary Braun, Relja Popovic, Jonathan D. Licht. Investigating the role of epigenetic mechanisms upon aberrant signaling network activation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Sup pl):Abstract nr 740. doi:10.1158/1538-7445.AM2013-740

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM2013-740

RVK:

XA 36000

RVK:

XA 10000

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2013

detail.hit.zdb_id: 2036785-5

detail.hit.zdb_id: 1432-1

detail.hit.zdb_id: 410466-3

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