Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma

Darko Bosnakovski; Elizabeth T. Ener; Mark S. Cooper; Micah D. Gearhart; Kevin A. Knights; Natalie C. Xu; Christian A. Palumbo; Erik A. Toso; Graham P. Marsh; Hannah J. Maple; Michael Kyba

doi:10.1038/s41389-021-00357-4

Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma

Darko Bosnakovski, Elizabeth T. Ener, Mark S. Cooper, Micah D. Gearhart, Kevin A. Knights, Natalie C. Xu, Christian A. Palumbo, Erik A. Toso, Graham P. Marsh, Hannah J. Maple, Michael Kyba

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

CIC-DUX4 sarcoma (CDS) is a highly aggressive and metastatic small round type of predominantly pediatric sarcoma driven by a fusion oncoprotein comprising the transcriptional repressor Capicua (CIC) fused to the C-terminal transcriptional activation domain of DUX4. CDS rapidly develops resistance to chemotherapy, thus novel specific therapies are greatly needed. We demonstrate that CIC-DUX4 requires P300/CBP to induce histone H3 acetylation, activate its targets, and drive oncogenesis. We describe the synthetic route to a selective and highly potent P300/CBP inhibitor named iP300w and related stereoisomers, and find that iP300w efficiently suppresses CIC-DUX4 transcriptional activity and reverses CIC-DUX4 induced acetylation. iP300w is active at 100-fold lower concentrations than related stereoisomers or A-485. At low doses, iP300w shows specificity to CDS cancer cell lines, rapidly inducing cell cycle arrest and preventing growth of established CDS xenograft tumors when delivered in vivo. The effectiveness of iP300w to inactivate CIC-DUX4 highlights a promising therapeutic opportunity for CDS.

Original language	English (US)
Article number	68
Journal	Oncogenesis
Volume	10
Issue number	10
DOIs	https://doi.org/10.1038/s41389-021-00357-4
State	Published - Oct 2021

Bibliographical note

Funding Information:
This work was supported by grants from the Children’s Cancer Research Fund (Research Grant Award 2020 and Project Grant 2021), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR055685). The authors would like to acknowledge Dr Michael Hall and Dr Michael Probert, Indicatrix Crystallography, for crystallisation and single crystal x-ray diffraction measurements; Madison Douglas, Varun Goal, Johannes Weiblen, and Ben Mai for assistance with data analysis and animal maintenance; Takuro Nakamura, Japanese Foundation for Cancer Research for providing the DUX4-CIC viral expression vector; and Tadashi Kondo, National Cancer Centre, Japan; Hidetatsu Otani, Osaka University, Japan; Michael Verneris, University of Colorado; and Masato Yamamoto and Eric Hendrickson, University of Minnesota for provision of cell lines.

Publisher Copyright:
© 2021, The Author(s).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1038/s41389-021-00357-4

Find It

Find It at U of M Libraries

Cite this

@article{8847365f2fd04d39b1ef00a714cf326e,

title = "Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma",

abstract = "CIC-DUX4 sarcoma (CDS) is a highly aggressive and metastatic small round type of predominantly pediatric sarcoma driven by a fusion oncoprotein comprising the transcriptional repressor Capicua (CIC) fused to the C-terminal transcriptional activation domain of DUX4. CDS rapidly develops resistance to chemotherapy, thus novel specific therapies are greatly needed. We demonstrate that CIC-DUX4 requires P300/CBP to induce histone H3 acetylation, activate its targets, and drive oncogenesis. We describe the synthetic route to a selective and highly potent P300/CBP inhibitor named iP300w and related stereoisomers, and find that iP300w efficiently suppresses CIC-DUX4 transcriptional activity and reverses CIC-DUX4 induced acetylation. iP300w is active at 100-fold lower concentrations than related stereoisomers or A-485. At low doses, iP300w shows specificity to CDS cancer cell lines, rapidly inducing cell cycle arrest and preventing growth of established CDS xenograft tumors when delivered in vivo. The effectiveness of iP300w to inactivate CIC-DUX4 highlights a promising therapeutic opportunity for CDS.",

author = "Darko Bosnakovski and Ener, {Elizabeth T.} and Cooper, {Mark S.} and Gearhart, {Micah D.} and Knights, {Kevin A.} and Xu, {Natalie C.} and Palumbo, {Christian A.} and Toso, {Erik A.} and Marsh, {Graham P.} and Maple, {Hannah J.} and Michael Kyba",

note = "Funding Information: This work was supported by grants from the Children{\textquoteright}s Cancer Research Fund (Research Grant Award 2020 and Project Grant 2021), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR055685). The authors would like to acknowledge Dr Michael Hall and Dr Michael Probert, Indicatrix Crystallography, for crystallisation and single crystal x-ray diffraction measurements; Madison Douglas, Varun Goal, Johannes Weiblen, and Ben Mai for assistance with data analysis and animal maintenance; Takuro Nakamura, Japanese Foundation for Cancer Research for providing the DUX4-CIC viral expression vector; and Tadashi Kondo, National Cancer Centre, Japan; Hidetatsu Otani, Osaka University, Japan; Michael Verneris, University of Colorado; and Masato Yamamoto and Eric Hendrickson, University of Minnesota for provision of cell lines. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = oct,

doi = "10.1038/s41389-021-00357-4",

language = "English (US)",

volume = "10",

journal = "Oncogenesis",

issn = "2157-9024",

publisher = "Springer Nature",

number = "10",

}

TY - JOUR

T1 - Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma

AU - Bosnakovski, Darko

AU - Ener, Elizabeth T.

AU - Cooper, Mark S.

AU - Gearhart, Micah D.

AU - Knights, Kevin A.

AU - Xu, Natalie C.

AU - Palumbo, Christian A.

AU - Toso, Erik A.

AU - Marsh, Graham P.

AU - Maple, Hannah J.

AU - Kyba, Michael

N1 - Funding Information: This work was supported by grants from the Children’s Cancer Research Fund (Research Grant Award 2020 and Project Grant 2021), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR055685). The authors would like to acknowledge Dr Michael Hall and Dr Michael Probert, Indicatrix Crystallography, for crystallisation and single crystal x-ray diffraction measurements; Madison Douglas, Varun Goal, Johannes Weiblen, and Ben Mai for assistance with data analysis and animal maintenance; Takuro Nakamura, Japanese Foundation for Cancer Research for providing the DUX4-CIC viral expression vector; and Tadashi Kondo, National Cancer Centre, Japan; Hidetatsu Otani, Osaka University, Japan; Michael Verneris, University of Colorado; and Masato Yamamoto and Eric Hendrickson, University of Minnesota for provision of cell lines. Publisher Copyright: © 2021, The Author(s).

PY - 2021/10

Y1 - 2021/10

N2 - CIC-DUX4 sarcoma (CDS) is a highly aggressive and metastatic small round type of predominantly pediatric sarcoma driven by a fusion oncoprotein comprising the transcriptional repressor Capicua (CIC) fused to the C-terminal transcriptional activation domain of DUX4. CDS rapidly develops resistance to chemotherapy, thus novel specific therapies are greatly needed. We demonstrate that CIC-DUX4 requires P300/CBP to induce histone H3 acetylation, activate its targets, and drive oncogenesis. We describe the synthetic route to a selective and highly potent P300/CBP inhibitor named iP300w and related stereoisomers, and find that iP300w efficiently suppresses CIC-DUX4 transcriptional activity and reverses CIC-DUX4 induced acetylation. iP300w is active at 100-fold lower concentrations than related stereoisomers or A-485. At low doses, iP300w shows specificity to CDS cancer cell lines, rapidly inducing cell cycle arrest and preventing growth of established CDS xenograft tumors when delivered in vivo. The effectiveness of iP300w to inactivate CIC-DUX4 highlights a promising therapeutic opportunity for CDS.

AB - CIC-DUX4 sarcoma (CDS) is a highly aggressive and metastatic small round type of predominantly pediatric sarcoma driven by a fusion oncoprotein comprising the transcriptional repressor Capicua (CIC) fused to the C-terminal transcriptional activation domain of DUX4. CDS rapidly develops resistance to chemotherapy, thus novel specific therapies are greatly needed. We demonstrate that CIC-DUX4 requires P300/CBP to induce histone H3 acetylation, activate its targets, and drive oncogenesis. We describe the synthetic route to a selective and highly potent P300/CBP inhibitor named iP300w and related stereoisomers, and find that iP300w efficiently suppresses CIC-DUX4 transcriptional activity and reverses CIC-DUX4 induced acetylation. iP300w is active at 100-fold lower concentrations than related stereoisomers or A-485. At low doses, iP300w shows specificity to CDS cancer cell lines, rapidly inducing cell cycle arrest and preventing growth of established CDS xenograft tumors when delivered in vivo. The effectiveness of iP300w to inactivate CIC-DUX4 highlights a promising therapeutic opportunity for CDS.

UR - http://www.scopus.com/inward/record.url?scp=85117404688&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85117404688&partnerID=8YFLogxK

U2 - 10.1038/s41389-021-00357-4

DO - 10.1038/s41389-021-00357-4

M3 - Article

C2 - 34642317

AN - SCOPUS:85117404688

SN - 2157-9024

VL - 10

JO - Oncogenesis

JF - Oncogenesis

IS - 10

M1 - 68

ER -

Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma

Abstract

Bibliographical note

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

Cite this