Atypical plant homeodomain of UBR7 functions as an H2BK120Ub ligase and breast tumor suppressor

Santanu Adhikary; Deepavali Chakravarti; Christopher Terranova; Isha Sengupta; Mayinuer Maitituoheti; Anirban Dasgupta; Dushyant Kumar Srivastava; Junsheng Ma; Ayush T. Raman; Emily Tarco; Aysegul A. Sahin; Roland Bassett; Fei Yang; Coya Tapia; Siddhartha Roy; Kunal Rai; Chandrima Das

doi:10.1038/s41467-019-08986-5

Atypical plant homeodomain of UBR7 functions as an H2BK120Ub ligase and breast tumor suppressor

Santanu Adhikary, Deepavali Chakravarti, Christopher Terranova, Isha Sengupta, Mayinuer Maitituoheti, Anirban Dasgupta, Dushyant Kumar Srivastava, Junsheng Ma, Ayush T. Raman, Emily Tarco, Aysegul A. Sahin, Roland Bassett, Fei Yang, Coya Tapia, Siddhartha Roy, Kunal Rai, Chandrima Das

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Abstract

The roles of Plant Homeodomain (PHD) fingers in catalysis of histone modifications are unknown. We demonstrated that the PHD finger of Ubiquitin Protein Ligase E3 Component N-Recognin7 (UBR7) harbors E3 ubiquitin ligase activity toward monoubiquitination of histone H2B at lysine120 (H2BK120Ub). Purified PHD finger or full-length UBR7 monoubiquitinated H2BK120 in vitro, and loss of UBR7 drastically reduced H2BK120Ub genome-wide binding sites in MCF10A cells. Low UBR7 expression was correlated with occurrence of triple-negative breast cancer and metastatic tumors. Consistently, UBR7 knockdown enhanced the invasiveness, induced epithelial-to-mesenchymal transition and promoted metastasis. Conversely, ectopic expression of UBR7 restored these cellular phenotypes and reduced tumor growth. Mechanistically, UBR7 loss reduced H2BK120Ub levels on cell adhesion genes, including CDH4, and upregulated the Wnt/β-Catenin signaling pathway. CDH4 overexpression could partially revert UBR7-dependent cellular phenotypes. Collectively, our results established UBR7 as a histone H2B monoubiquitin ligase that suppresses tumorigenesis and metastasis of triple-negative breast cancer.

Original language	English (US)
Article number	1398
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-08986-5
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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Adhikary, S., Chakravarti, D., Terranova, C., Sengupta, I., Maitituoheti, M., Dasgupta, A., Srivastava, D. K., Ma, J., Raman, A. T., Tarco, E., Sahin, A. A., Bassett, R., Yang, F., Tapia, C., Roy, S., Rai, K., & Das, C. (2019). Atypical plant homeodomain of UBR7 functions as an H2BK120Ub ligase and breast tumor suppressor. Nature communications, 10(1), Article 1398. https://doi.org/10.1038/s41467-019-08986-5

Adhikary, S, Chakravarti, D, Terranova, C, Sengupta, I, Maitituoheti, M, Dasgupta, A, Srivastava, DK, Ma, J, Raman, AT, Tarco, E, Sahin, AA , Bassett, R, Yang, F, Tapia, C, Roy, S, Rai, K & Das, C 2019, 'Atypical plant homeodomain of UBR7 functions as an H2BK120Ub ligase and breast tumor suppressor', Nature communications, vol. 10, no. 1, 1398. https://doi.org/10.1038/s41467-019-08986-5

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title = "Atypical plant homeodomain of UBR7 functions as an H2BK120Ub ligase and breast tumor suppressor",

abstract = "The roles of Plant Homeodomain (PHD) fingers in catalysis of histone modifications are unknown. We demonstrated that the PHD finger of Ubiquitin Protein Ligase E3 Component N-Recognin7 (UBR7) harbors E3 ubiquitin ligase activity toward monoubiquitination of histone H2B at lysine120 (H2BK120Ub). Purified PHD finger or full-length UBR7 monoubiquitinated H2BK120 in vitro, and loss of UBR7 drastically reduced H2BK120Ub genome-wide binding sites in MCF10A cells. Low UBR7 expression was correlated with occurrence of triple-negative breast cancer and metastatic tumors. Consistently, UBR7 knockdown enhanced the invasiveness, induced epithelial-to-mesenchymal transition and promoted metastasis. Conversely, ectopic expression of UBR7 restored these cellular phenotypes and reduced tumor growth. Mechanistically, UBR7 loss reduced H2BK120Ub levels on cell adhesion genes, including CDH4, and upregulated the Wnt/β-Catenin signaling pathway. CDH4 overexpression could partially revert UBR7-dependent cellular phenotypes. Collectively, our results established UBR7 as a histone H2B monoubiquitin ligase that suppresses tumorigenesis and metastasis of triple-negative breast cancer.",

author = "Santanu Adhikary and Deepavali Chakravarti and Christopher Terranova and Isha Sengupta and Mayinuer Maitituoheti and Anirban Dasgupta and Srivastava, {Dushyant Kumar} and Junsheng Ma and Raman, {Ayush T.} and Emily Tarco and Sahin, {Aysegul A.} and Roland Bassett and Fei Yang and Coya Tapia and Siddhartha Roy and Kunal Rai and Chandrima Das",

note = "Funding Information: We thank Prof. Robert G. Roeder and Prof. Moshe Oren for providing us with the FLAG H2B wild-type and K120R mutant plasmids and RNF20 shRNA plasmid, respectively. We thank Drs. Michelle C. Barton, Jessica Tyler, and Tapas K. Kundu for critical comments on the manuscript. We acknowledge Scientific Editing team at MD Anderson Cancer Center for proofreading our manuscript. This work was supported in part by research grants from Biomolecular Assembly, Recognition and Dynamics Project (Grant 12-R&D-SIN-5.04-0103) from the Department of Atomic Energy, Swarnajayanti Fellowship, Department of Science and Technology and Ramalingaswami Fellowship, Department of Biotechnology, Government of India to C.D.; CSIR-Network Project (UNSEEN) and Ramanujan fellowship, Department of Science and Technology, Government of India to S.R.; and National Cancer Institute grant (CA160578) and The University of Texas MD Anderson Cancer Center (start-up funds) to K.R. S.A., A.D., and D.K.S. thank the Council for Scientific and Industrial Research, University Grants Commission and Indian Council for Medical Research, Government of India, respectively, for funding their fellowship. D.C. is supported by the Triumph post-doctoral training program at MD Anderson Cancer Center supported by CPRIT (RP170067). Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

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doi = "10.1038/s41467-019-08986-5",

language = "English (US)",

volume = "10",

journal = "Nature communications",

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T1 - Atypical plant homeodomain of UBR7 functions as an H2BK120Ub ligase and breast tumor suppressor

AU - Adhikary, Santanu

AU - Chakravarti, Deepavali

AU - Terranova, Christopher

AU - Sengupta, Isha

AU - Maitituoheti, Mayinuer

AU - Dasgupta, Anirban

AU - Srivastava, Dushyant Kumar

AU - Ma, Junsheng

AU - Raman, Ayush T.

AU - Tarco, Emily

AU - Sahin, Aysegul A.

AU - Bassett, Roland

AU - Yang, Fei

AU - Tapia, Coya

AU - Roy, Siddhartha

AU - Rai, Kunal

AU - Das, Chandrima

N1 - Funding Information: We thank Prof. Robert G. Roeder and Prof. Moshe Oren for providing us with the FLAG H2B wild-type and K120R mutant plasmids and RNF20 shRNA plasmid, respectively. We thank Drs. Michelle C. Barton, Jessica Tyler, and Tapas K. Kundu for critical comments on the manuscript. We acknowledge Scientific Editing team at MD Anderson Cancer Center for proofreading our manuscript. This work was supported in part by research grants from Biomolecular Assembly, Recognition and Dynamics Project (Grant 12-R&D-SIN-5.04-0103) from the Department of Atomic Energy, Swarnajayanti Fellowship, Department of Science and Technology and Ramalingaswami Fellowship, Department of Biotechnology, Government of India to C.D.; CSIR-Network Project (UNSEEN) and Ramanujan fellowship, Department of Science and Technology, Government of India to S.R.; and National Cancer Institute grant (CA160578) and The University of Texas MD Anderson Cancer Center (start-up funds) to K.R. S.A., A.D., and D.K.S. thank the Council for Scientific and Industrial Research, University Grants Commission and Indian Council for Medical Research, Government of India, respectively, for funding their fellowship. D.C. is supported by the Triumph post-doctoral training program at MD Anderson Cancer Center supported by CPRIT (RP170067). Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - The roles of Plant Homeodomain (PHD) fingers in catalysis of histone modifications are unknown. We demonstrated that the PHD finger of Ubiquitin Protein Ligase E3 Component N-Recognin7 (UBR7) harbors E3 ubiquitin ligase activity toward monoubiquitination of histone H2B at lysine120 (H2BK120Ub). Purified PHD finger or full-length UBR7 monoubiquitinated H2BK120 in vitro, and loss of UBR7 drastically reduced H2BK120Ub genome-wide binding sites in MCF10A cells. Low UBR7 expression was correlated with occurrence of triple-negative breast cancer and metastatic tumors. Consistently, UBR7 knockdown enhanced the invasiveness, induced epithelial-to-mesenchymal transition and promoted metastasis. Conversely, ectopic expression of UBR7 restored these cellular phenotypes and reduced tumor growth. Mechanistically, UBR7 loss reduced H2BK120Ub levels on cell adhesion genes, including CDH4, and upregulated the Wnt/β-Catenin signaling pathway. CDH4 overexpression could partially revert UBR7-dependent cellular phenotypes. Collectively, our results established UBR7 as a histone H2B monoubiquitin ligase that suppresses tumorigenesis and metastasis of triple-negative breast cancer.

AB - The roles of Plant Homeodomain (PHD) fingers in catalysis of histone modifications are unknown. We demonstrated that the PHD finger of Ubiquitin Protein Ligase E3 Component N-Recognin7 (UBR7) harbors E3 ubiquitin ligase activity toward monoubiquitination of histone H2B at lysine120 (H2BK120Ub). Purified PHD finger or full-length UBR7 monoubiquitinated H2BK120 in vitro, and loss of UBR7 drastically reduced H2BK120Ub genome-wide binding sites in MCF10A cells. Low UBR7 expression was correlated with occurrence of triple-negative breast cancer and metastatic tumors. Consistently, UBR7 knockdown enhanced the invasiveness, induced epithelial-to-mesenchymal transition and promoted metastasis. Conversely, ectopic expression of UBR7 restored these cellular phenotypes and reduced tumor growth. Mechanistically, UBR7 loss reduced H2BK120Ub levels on cell adhesion genes, including CDH4, and upregulated the Wnt/β-Catenin signaling pathway. CDH4 overexpression could partially revert UBR7-dependent cellular phenotypes. Collectively, our results established UBR7 as a histone H2B monoubiquitin ligase that suppresses tumorigenesis and metastasis of triple-negative breast cancer.

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Atypical plant homeodomain of UBR7 functions as an H2BK120Ub ligase and breast tumor suppressor

Abstract

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