Oncotarget

Research Papers:

Cullin 3SPOP ubiquitin E3 ligase promotes the poly-ubiquitination and degradation of HDAC6

Yuyong Tan, Yanpeng Ci, Xiangpeng Dai, Fei Wu, Jianping Guo, Deliang Liu, Brian J. North _, Jirong Huo and Jinfang Zhang

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Oncotarget. 2017; 8:47890-47901. https://doi.org/10.18632/oncotarget.18141

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Abstract

Yuyong Tan1,2, Yanpeng Ci2,3, Xiangpeng Dai2, Fei Wu2,4, Jianping Guo2, Deliang Liu1, Brian J. North2, Jirong Huo1 and Jinfang Zhang2

1Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha 410011, P.R. China

2Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA

3School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, P.R. China

4Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China

Correspondence to:

Brian J. North, email: bnorth@bidmc.harvard.edu

Jirong Huo, email: hjr198@hotmail.com

Jinfang Zhang, email: jzhang17@bidmc.harvard.edu

Keywords: HDAC6, SPOP, Cullin 3, ubiquitination, tumorigenesis

Received: March 29, 2017    Accepted: April 15, 2017    Published: May 24, 2017

ABSTRACT

The histone deacetylase 6 (HDAC6) plays critical roles in human tumorigenesis and metastasis. As such, HDAC6-selective inhibitors have entered clinical trials for cancer therapy. However, the upstream regulator(s), especially ubiquitin E3 ligase(s), responsible for controlling the protein stability of HDAC6 remains largely undefined. Here, we report that Cullin 3SPOP earmarks HDAC6 for poly-ubiquitination and degradation. We found that the proteasome inhibitor MG132, or the Cullin-based E3 ligases inhibitor MLN4924, but not the autophagosome-lysosome inhibitor bafilomycin A1, stabilized endogenous HDAC6 protein in multiple cancer cell lines. Furthermore, we demonstrated that Cullin 3-based ubiquitin E3 ligase(s) primarily reduced the stability of HDAC6. Importantly, we identified SPOP, an adaptor protein of Cullin 3 family E3 ligases, specifically interacted with HDAC6, and promoted its poly-ubiquitination and subsequent degradation in cells. Notably, cancer-derived SPOP mutants disrupted their binding with HDAC6 and thereby failed to promote HDAC6 degradation. More importantly, increased cellular proliferation and migration in SPOP-depleted HCT116 colon cancer cells could be partly reversed by additional depletion of HDAC6, suggesting that HDAC6 is a key downstream effector for SPOP tumor suppressor function. Together, our data identify the tumor suppressor SPOP as an upstream negative regulator for HDAC6 stability, and SPOP loss-of-function mutations might lead to elevated levels of the HDAC6 oncoprotein to facilitate tumorigenesis and metastasis in various human cancers.


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