OTUB2 Promotes Cancer Metastasis via Hippo-Independent Activation of YAP and TAZ

Zhengkui Zhang; Jinjin Du; Shuai Wang; Li Shao; Ke Jin; Fang Li; Bajin Wei; Wei Ding; Peifen Fu; Hans van Dam; Aijun Wang; Jin Jin; Chen Ding; Bing Yang; Min Zheng; Xin-Hua Feng; Kun-Liang Guan; Long Zhang

doi:10.1016/j.molcel.2018.10.030

OTUB2 Promotes Cancer Metastasis via Hippo-Independent Activation of YAP and TAZ

Mol Cell. 2019 Jan 3;73(1):7-21.e7. doi: 10.1016/j.molcel.2018.10.030. Epub 2018 Nov 21.

Authors

Zhengkui Zhang¹, Jinjin Du², Shuai Wang³, Li Shao⁴, Ke Jin², Fang Li², Bajin Wei⁵, Wei Ding⁵, Peifen Fu⁵, Hans van Dam⁶, Aijun Wang⁷, Jin Jin², Chen Ding⁸, Bing Yang², Min Zheng⁴, Xin-Hua Feng², Kun-Liang Guan⁹, Long Zhang¹⁰

Affiliations

¹ MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215006, China.
² MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
³ Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215006, China.
⁴ State Key Laboratory for Diagnostic and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Hangzhou 310000, China.
⁵ Breast Disease Center, First Affiliated Hospital of Medicine College of Zhejiang University, Hangzhou 310006, China.
⁶ Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
⁷ Department of Surgery, School of Medicine, UC Davis, Davis, CA 95817, USA.
⁸ State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Fudan University, 200433 Shanghai, China.
⁹ Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 94158, USA.
¹⁰ MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China. Electronic address: l_zhang@zju.edu.cn.

PMID: 30472188
DOI: 10.1016/j.molcel.2018.10.030

Abstract

The transcriptional regulators YAP and TAZ play important roles in development, physiology, and tumorigenesis and are negatively controlled by the Hippo pathway. It is yet unknown why the YAP/ TAZ proteins are frequently activated in human malignancies in which the Hippo pathway is still active. Here, by a gain-of-function cancer metastasis screen, we discovered OTUB2 as a cancer stemness and metastasis-promoting factor that deubiquitinates and activates YAP/TAZ. We found OTUB2 to be poly-SUMOylated on lysine 233, and this SUMOylation enables it to bind YAP/TAZ. We also identified a yet-unknown SUMO-interacting motif (SIM) in YAP and TAZ required for their association with SUMOylated OTUB2. Importantly, EGF and oncogenic KRAS induce OTUB2 poly-SUMOylation and thereby activate YAP/TAZ. Our results establish OTUB2 as an essential modulator of YAP/TAZ and also reveal a novel mechanism via which YAP/TAZ activity is induced by oncogenic KRAS.

Keywords: OTUB2; SUMOylation; YAP/TAZ; deubiquitination; metastasis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Breast Neoplasms / enzymology*
Breast Neoplasms / genetics
Breast Neoplasms / pathology
Cell Differentiation
Cell Line, Tumor
Cell Movement* / drug effects
Epidermal Growth Factor / pharmacology
ErbB Receptors / agonists
ErbB Receptors / metabolism
Female
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Lysine
Mice, Inbred BALB C
Mice, Nude
Mutation
Neoplasm Metastasis
Neoplastic Stem Cells / enzymology*
Neoplastic Stem Cells / pathology
Phenotype
Phosphoproteins / genetics
Phosphoproteins / metabolism*
Proteasome Endopeptidase Complex / metabolism
Protein Binding
Protein Interaction Domains and Motifs
Proteolysis
Proto-Oncogene Proteins p21(ras) / genetics
Signal Transduction
Sumoylation
Thiolester Hydrolases / genetics
Thiolester Hydrolases / metabolism*
Time Factors
Trans-Activators
Transcription Factors
Transcriptional Coactivator with PDZ-Binding Motif Proteins
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Intracellular Signaling Peptides and Proteins
KRAS protein, human
Phosphoproteins
Trans-Activators
Transcription Factors
Transcriptional Coactivator with PDZ-Binding Motif Proteins
WWTR1 protein, human
YAP-Signaling Proteins
YAP1 protein, human
Epidermal Growth Factor
EGFR protein, human
ErbB Receptors
OTUB2 protein, human
Thiolester Hydrolases
Proteasome Endopeptidase Complex
Proto-Oncogene Proteins p21(ras)
Lysine

Grants and funding

R35 CA196878/CA/NCI NIH HHS/United States