Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9

Bing Yu; Stephen Swatkoski; Alesia Holly; Liam C. Lee; Valentin Giroux; Chih Shia Lee; Dennis Hsu; Jordan L. Smith; Garmen Yuen; Junqiu Yue; David K. Ann; R. Mark Simpson; Chad J. Creighton; William D. Figg; Marjan Gucek; Ji Luo; Thomas M. Roberts

doi:10.1073/pnas.1415569112

Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9

Bing Yu, Stephen Swatkoski, Alesia Holly, Liam C. Lee, Valentin Giroux, Chih Shia Lee, Dennis Hsu, Jordan L. Smith, Garmen Yuen, Junqiu Yue, David K. Ann, R. Mark Simpson, Chad J. Creighton, William D. Figg, Marjan Gucek, Ji Luo^*, Thomas M. Roberts

^*Corresponding author for this work

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

58 Scopus citations

Abstract

The small GTPase KRAS is frequently mutated in human cancer and currently there are no targeted therapies for KRAS mutant tumors. Here, we show that the small ubiquitin-like modifier (SUMO) pathway is required for KRAS-driven transformation. RNAi depletion of the SUMO E2 ligase Ubc9 suppresses 3D growth of KRAS mutant colorectal cancer cells in vitro and attenuates tumor growth in vivo. In KRAS mutant cells, a subset of proteins exhibit elevated levels of SUMOylation. Among these proteins, KAP1, CHD1, and EIF3L collectively support anchorage-independent growth, and the SUMOylation of KAP1 is necessary for its activity in this context. Thus, the SUMO pathway critically contributes to the transformed phenotype of KRAS mutant cells and Ubc9 presents a potential target for the treatment of KRAS mutant colorectal cancer.

Original language	English
Pages (from-to)	E1724-E1733
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	112
Issue number	14
DOIs	https://doi.org/10.1073/pnas.1415569112
State	Published - 7 Apr 2015
Externally published	Yes

Keywords

Colorectal cancer
KRAS
SUMO
Transformation
Ubc9

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10.1073/pnas.1415569112

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Yu, B., Swatkoski, S., Holly, A., Lee, L. C., Giroux, V., Lee, C. S., Hsu, D., Smith, J. L., Yuen, G., Yue, J., Ann, D. K., Simpson, R. M., Creighton, C. J., Figg, W. D., Gucek, M., Luo, J., & Roberts, T. M. (2015). Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9. Proceedings of the National Academy of Sciences of the United States of America, 112(14), E1724-E1733. https://doi.org/10.1073/pnas.1415569112

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title = "Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9",

abstract = "The small GTPase KRAS is frequently mutated in human cancer and currently there are no targeted therapies for KRAS mutant tumors. Here, we show that the small ubiquitin-like modifier (SUMO) pathway is required for KRAS-driven transformation. RNAi depletion of the SUMO E2 ligase Ubc9 suppresses 3D growth of KRAS mutant colorectal cancer cells in vitro and attenuates tumor growth in vivo. In KRAS mutant cells, a subset of proteins exhibit elevated levels of SUMOylation. Among these proteins, KAP1, CHD1, and EIF3L collectively support anchorage-independent growth, and the SUMOylation of KAP1 is necessary for its activity in this context. Thus, the SUMO pathway critically contributes to the transformed phenotype of KRAS mutant cells and Ubc9 presents a potential target for the treatment of KRAS mutant colorectal cancer.",

keywords = "Colorectal cancer, KRAS, SUMO, Transformation, Ubc9",

author = "Bing Yu and Stephen Swatkoski and Alesia Holly and Lee, {Liam C.} and Valentin Giroux and Lee, {Chih Shia} and Dennis Hsu and Smith, {Jordan L.} and Garmen Yuen and Junqiu Yue and Ann, {David K.} and Simpson, {R. Mark} and Creighton, {Chad J.} and Figg, {William D.} and Marjan Gucek and Ji Luo and Roberts, {Thomas M.}",

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doi = "10.1073/pnas.1415569112",

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Yu, B, Swatkoski, S, Holly, A, Lee, LC, Giroux, V, Lee, CS, Hsu, D, Smith, JL, Yuen, G, Yue, J, Ann, DK, Simpson, RM, Creighton, CJ, Figg, WD, Gucek, M, Luo, J & Roberts, TM 2015, 'Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 14, pp. E1724-E1733. https://doi.org/10.1073/pnas.1415569112

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T1 - Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9

AU - Yu, Bing

AU - Swatkoski, Stephen

AU - Holly, Alesia

AU - Lee, Liam C.

AU - Giroux, Valentin

AU - Lee, Chih Shia

AU - Hsu, Dennis

AU - Smith, Jordan L.

AU - Yuen, Garmen

AU - Yue, Junqiu

AU - Ann, David K.

AU - Simpson, R. Mark

AU - Creighton, Chad J.

AU - Figg, William D.

AU - Gucek, Marjan

AU - Luo, Ji

AU - Roberts, Thomas M.

PY - 2015/4/7

Y1 - 2015/4/7

N2 - The small GTPase KRAS is frequently mutated in human cancer and currently there are no targeted therapies for KRAS mutant tumors. Here, we show that the small ubiquitin-like modifier (SUMO) pathway is required for KRAS-driven transformation. RNAi depletion of the SUMO E2 ligase Ubc9 suppresses 3D growth of KRAS mutant colorectal cancer cells in vitro and attenuates tumor growth in vivo. In KRAS mutant cells, a subset of proteins exhibit elevated levels of SUMOylation. Among these proteins, KAP1, CHD1, and EIF3L collectively support anchorage-independent growth, and the SUMOylation of KAP1 is necessary for its activity in this context. Thus, the SUMO pathway critically contributes to the transformed phenotype of KRAS mutant cells and Ubc9 presents a potential target for the treatment of KRAS mutant colorectal cancer.

AB - The small GTPase KRAS is frequently mutated in human cancer and currently there are no targeted therapies for KRAS mutant tumors. Here, we show that the small ubiquitin-like modifier (SUMO) pathway is required for KRAS-driven transformation. RNAi depletion of the SUMO E2 ligase Ubc9 suppresses 3D growth of KRAS mutant colorectal cancer cells in vitro and attenuates tumor growth in vivo. In KRAS mutant cells, a subset of proteins exhibit elevated levels of SUMOylation. Among these proteins, KAP1, CHD1, and EIF3L collectively support anchorage-independent growth, and the SUMOylation of KAP1 is necessary for its activity in this context. Thus, the SUMO pathway critically contributes to the transformed phenotype of KRAS mutant cells and Ubc9 presents a potential target for the treatment of KRAS mutant colorectal cancer.

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KW - SUMO

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JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 14

ER -

Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9

Abstract

Keywords

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