Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase

Stefanie Peter; Jennyfer Bultinck; Kevin Myant; Laura A Jaenicke; Susanne Walz; Judith Müller; Michael Gmachl; Matthias Treu; Guido Boehmelt; Carsten P Ade; Werner Schmitz; Armin Wiegering; Christoph Otto; Nikita Popov; Owen Sansom; Norbert Kraut; Martin Eilers

doi:10.15252/emmm.201403927

Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase

Stefanie Peter, Jennyfer Bultinck, Kevin Myant, Laura A Jaenicke, Susanne Walz, Judith Müller, Michael Gmachl, Matthias Treu, Guido Boehmelt, Carsten P Ade, Werner Schmitz, Armin Wiegering, Christoph Otto, Nikita Popov, Owen Sansom, Norbert Kraut, Martin Eilers

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

Abstract / Description of output

Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF-BP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high-throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells.

Original language	English
Pages (from-to)	1525-41
Number of pages	17
Journal	EMBO Molecular Medicine
Volume	6
Issue number	12
Early online date	24 Sept 2014
DOIs	https://doi.org/10.15252/emmm.201403927
Publication status	Published - Dec 2014

Keywords / Materials (for Non-textual outputs)

Animals
Cell Line, Tumor
Cell Proliferation
Colorectal Neoplasms
Gene Expression Regulation, Neoplastic
Humans
Kruppel-Like Transcription Factors
Mice
Mice, SCID
Oncogene Protein p55(v-myc)
Protein Binding
Small Molecule Libraries
Transcriptional Activation
Ubiquitin-Protein Ligases

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10.15252/emmm.201403927

Kevin Myant
- Deanery of Molecular, Genetic and Population Health Sciences - Reader
- Edinburgh Cancer Research Centre
Person: Academic: Research Active

Cite this

Peter, S., Bultinck, J., Myant, K., Jaenicke, L. A., Walz, S., Müller, J., Gmachl, M., Treu, M., Boehmelt, G., Ade, C. P., Schmitz, W., Wiegering, A., Otto, C., Popov, N., Sansom, O., Kraut, N., & Eilers, M. (2014). Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase. EMBO Molecular Medicine, 6(12), 1525-41. https://doi.org/10.15252/emmm.201403927

@article{498b89fea3c64e849db8f32d190cb3ee,

title = "Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase",

abstract = "Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF-BP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high-throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells.",

keywords = "Animals, Cell Line, Tumor, Cell Proliferation, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Humans, Kruppel-Like Transcription Factors, Mice, Mice, SCID, Oncogene Protein p55(v-myc), Protein Binding, Small Molecule Libraries, Transcriptional Activation, Ubiquitin-Protein Ligases",

author = "Stefanie Peter and Jennyfer Bultinck and Kevin Myant and Jaenicke, {Laura A} and Susanne Walz and Judith M{\"u}ller and Michael Gmachl and Matthias Treu and Guido Boehmelt and Ade, {Carsten P} and Werner Schmitz and Armin Wiegering and Christoph Otto and Nikita Popov and Owen Sansom and Norbert Kraut and Martin Eilers",

note = "{\textcopyright} 2014 The Authors. Published under the terms of the CC BY 4.0 license.",

year = "2014",

month = dec,

doi = "10.15252/emmm.201403927",

language = "English",

volume = "6",

pages = "1525--41",

journal = "EMBO Molecular Medicine",

issn = "1757-4676",

publisher = "Wiley-Blackwell",

number = "12",

}

Peter, S, Bultinck, J, Myant, K, Jaenicke, LA, Walz, S, Müller, J, Gmachl, M, Treu, M, Boehmelt, G, Ade, CP, Schmitz, W, Wiegering, A, Otto, C, Popov, N, Sansom, O, Kraut, N & Eilers, M 2014, 'Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase', EMBO Molecular Medicine, vol. 6, no. 12, pp. 1525-41. https://doi.org/10.15252/emmm.201403927

TY - JOUR

T1 - Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase

AU - Peter, Stefanie

AU - Bultinck, Jennyfer

AU - Myant, Kevin

AU - Jaenicke, Laura A

AU - Walz, Susanne

AU - Müller, Judith

AU - Gmachl, Michael

AU - Treu, Matthias

AU - Boehmelt, Guido

AU - Ade, Carsten P

AU - Schmitz, Werner

AU - Wiegering, Armin

AU - Otto, Christoph

AU - Popov, Nikita

AU - Sansom, Owen

AU - Kraut, Norbert

AU - Eilers, Martin

PY - 2014/12

Y1 - 2014/12

N2 - Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF-BP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high-throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells.

AB - Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF-BP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high-throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells.

KW - Animals

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Colorectal Neoplasms

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Kruppel-Like Transcription Factors

KW - Mice

KW - Mice, SCID

KW - Oncogene Protein p55(v-myc)

KW - Protein Binding

KW - Small Molecule Libraries

KW - Transcriptional Activation

KW - Ubiquitin-Protein Ligases

U2 - 10.15252/emmm.201403927

DO - 10.15252/emmm.201403927

M3 - Article

C2 - 25253726

SN - 1757-4676

VL - 6

SP - 1525

EP - 1541

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 12

ER -

Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

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Kevin Myant

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