Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple negative breast cancer

Giada Zurlo; Xijuan Liu; Mamoru Takada; Cheng Fan; Jeremy M. Simon; Travis S. Ptacek; Javier Rodriguez; Alex von Kriegsheim; Juan Liu; Jason W. Locasale; Adam Robinson; Jing Zhang; Jessica M. Holler; Baek Kim; Marie Zikánová; Jörgen Bierau; Ling Xie; Xian Chen; Mingjie Li; Charles M. Perou; Qing Zhang

doi:10.1038/s41467-019-13168-4

Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple negative breast cancer

Giada Zurlo, Xijuan Liu, Mamoru Takada, Cheng Fan, Jeremy M. Simon, Travis S. Ptacek, Javier Rodriguez, Alex von Kriegsheim, Juan Liu, Jason W. Locasale, Adam Robinson, Jing Zhang, Jessica M. Holler, Baek Kim, Marie Zikánová, Jörgen Bierau, Ling Xie, Xian Chen, Mingjie Li, Charles M. PerouQing Zhang

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23 Scopus citations

Abstract

Protein hydroxylation affects protein stability, activity, and interactome, therefore contributing to various diseases including cancers. However, the transiency of the hydroxylation reaction hinders the identification of hydroxylase substrates. By developing an enzyme-substrate trapping strategy coupled with TAP-TAG or orthogonal GST- purification followed by mass spectrometry, we identify adenylosuccinate lyase (ADSL) as an EglN2 hydroxylase substrate in triple negative breast cancer (TNBC). ADSL expression is higher in TNBC than other breast cancer subtypes or normal breast tissues. ADSL knockout impairs TNBC cell proliferation and invasiveness in vitro and in vivo. An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. Hydroxylation-proficient ADSL, by affecting adenosine levels, represses the expression of the long non-coding RNA MIR22HG, thus upregulating cMYC protein level. Our findings highlight the role of ADSL hydroxylation in controlling cMYC and TNBC tumorigenesis.

Original language	English (US)
Article number	5177
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13168-4
State	Published - Dec 1 2019

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Zurlo, G., Liu, X., Takada, M., Fan, C., Simon, J. M., Ptacek, T. S., Rodriguez, J., von Kriegsheim, A., Liu, J., Locasale, J. W., Robinson, A., Zhang, J., Holler, J. M., Kim, B., Zikánová, M., Bierau, J., Xie, L., Chen, X., Li, M., ... Zhang, Q. (2019). Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple negative breast cancer. Nature communications, 10(1), Article 5177. https://doi.org/10.1038/s41467-019-13168-4

Zurlo, G, Liu, X, Takada, M, Fan, C, Simon, JM, Ptacek, TS, Rodriguez, J, von Kriegsheim, A, Liu, J, Locasale, JW, Robinson, A, Zhang, J, Holler, JM, Kim, B, Zikánová, M, Bierau, J, Xie, L, Chen, X, Li, M, Perou, CM & Zhang, Q 2019, 'Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple negative breast cancer', Nature communications, vol. 10, no. 1, 5177. https://doi.org/10.1038/s41467-019-13168-4

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title = "Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple negative breast cancer",

abstract = "Protein hydroxylation affects protein stability, activity, and interactome, therefore contributing to various diseases including cancers. However, the transiency of the hydroxylation reaction hinders the identification of hydroxylase substrates. By developing an enzyme-substrate trapping strategy coupled with TAP-TAG or orthogonal GST- purification followed by mass spectrometry, we identify adenylosuccinate lyase (ADSL) as an EglN2 hydroxylase substrate in triple negative breast cancer (TNBC). ADSL expression is higher in TNBC than other breast cancer subtypes or normal breast tissues. ADSL knockout impairs TNBC cell proliferation and invasiveness in vitro and in vivo. An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. Hydroxylation-proficient ADSL, by affecting adenosine levels, represses the expression of the long non-coding RNA MIR22HG, thus upregulating cMYC protein level. Our findings highlight the role of ADSL hydroxylation in controlling cMYC and TNBC tumorigenesis.",

author = "Giada Zurlo and Xijuan Liu and Mamoru Takada and Cheng Fan and Simon, {Jeremy M.} and Ptacek, {Travis S.} and Javier Rodriguez and {von Kriegsheim}, Alex and Juan Liu and Locasale, {Jason W.} and Adam Robinson and Jing Zhang and Holler, {Jessica M.} and Baek Kim and Marie Zik{\'a}nov{\'a} and J{\"o}rgen Bierau and Ling Xie and Xian Chen and Mingjie Li and Perou, {Charles M.} and Qing Zhang",

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AU - Zurlo, Giada

AU - Liu, Xijuan

AU - Takada, Mamoru

AU - Fan, Cheng

AU - Simon, Jeremy M.

AU - Ptacek, Travis S.

AU - Rodriguez, Javier

AU - von Kriegsheim, Alex

AU - Liu, Juan

AU - Locasale, Jason W.

AU - Robinson, Adam

AU - Zhang, Jing

AU - Holler, Jessica M.

AU - Kim, Baek

AU - Zikánová, Marie

AU - Bierau, Jörgen

AU - Xie, Ling

AU - Chen, Xian

AU - Li, Mingjie

AU - Perou, Charles M.

AU - Zhang, Qing

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Protein hydroxylation affects protein stability, activity, and interactome, therefore contributing to various diseases including cancers. However, the transiency of the hydroxylation reaction hinders the identification of hydroxylase substrates. By developing an enzyme-substrate trapping strategy coupled with TAP-TAG or orthogonal GST- purification followed by mass spectrometry, we identify adenylosuccinate lyase (ADSL) as an EglN2 hydroxylase substrate in triple negative breast cancer (TNBC). ADSL expression is higher in TNBC than other breast cancer subtypes or normal breast tissues. ADSL knockout impairs TNBC cell proliferation and invasiveness in vitro and in vivo. An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. Hydroxylation-proficient ADSL, by affecting adenosine levels, represses the expression of the long non-coding RNA MIR22HG, thus upregulating cMYC protein level. Our findings highlight the role of ADSL hydroxylation in controlling cMYC and TNBC tumorigenesis.

AB - Protein hydroxylation affects protein stability, activity, and interactome, therefore contributing to various diseases including cancers. However, the transiency of the hydroxylation reaction hinders the identification of hydroxylase substrates. By developing an enzyme-substrate trapping strategy coupled with TAP-TAG or orthogonal GST- purification followed by mass spectrometry, we identify adenylosuccinate lyase (ADSL) as an EglN2 hydroxylase substrate in triple negative breast cancer (TNBC). ADSL expression is higher in TNBC than other breast cancer subtypes or normal breast tissues. ADSL knockout impairs TNBC cell proliferation and invasiveness in vitro and in vivo. An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. Hydroxylation-proficient ADSL, by affecting adenosine levels, represses the expression of the long non-coding RNA MIR22HG, thus upregulating cMYC protein level. Our findings highlight the role of ADSL hydroxylation in controlling cMYC and TNBC tumorigenesis.

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Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple negative breast cancer

Abstract

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