The HECTD3 E3 ubiquitin ligase facilitates cancer cell survival by promoting K63-linked polyubiquitination of caspase-8

Y. Li; Y. Kong; Z. Zhou; H. Chen; Z. Wang; Y. C. Hsieh; D. Zhao; X. Zhi; J. Huang; J. Zhang; H. Li; C. Chen

doi:10.1038/cddis.2013.464

The HECTD3 E3 ubiquitin ligase facilitates cancer cell survival by promoting K63-linked polyubiquitination of caspase-8

Y. Li
, Y. Kong
, Z. Zhou
, H. Chen
, Z. Wang
, Y. C. Hsieh
, D. Zhao
, X. Zhi
, J. Huang
, J. Zhang
, H. Li
, C. Chen

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

60 Scopus citations

Abstract

Apoptosis resistance is a hurdle for cancer treatment. HECTD3, a new E3 ubiquitin ligase, interacts with caspase-8 death effector domains and ubiquitinates caspase-8 with K63-linked polyubiquitin chains that do not target caspase-8 for degradation but decrease the caspase-8 activation. HECTD3 depletion can sensitize cancer cells to extrinsic apoptotic stimuli. In addition, HECTD3 inhibits TNF-related apoptosis-inducing ligand (TRAIL)-induced caspase-8 cleavage in an E3 ligase activity-dependent manner. Mutation of the caspase-8 ubiquitination site at K215 abolishes the HECTD3 protection from TRAIL-induced cleavage. Finally, HECTD3 is frequently overexpressed in breast carcinomas. These findings suggest that caspase-8 ubiquitination by HECTD3 confers cancer cell survival.

Original language	English (US)
Article number	e935
Journal	Cell Death and Disease
Volume	4
Issue number	11
DOIs	https://doi.org/10.1038/cddis.2013.464
State	Published - Nov 2013
Externally published	Yes

Keywords

Apoptosis
Breast cancer
Caspase-8
HECTD3
Ubiquitination

ASJC Scopus subject areas

Immunology
Cellular and Molecular Neuroscience
Cell Biology
Cancer Research

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10.1038/cddis.2013.464

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title = "The HECTD3 E3 ubiquitin ligase facilitates cancer cell survival by promoting K63-linked polyubiquitination of caspase-8",

abstract = "Apoptosis resistance is a hurdle for cancer treatment. HECTD3, a new E3 ubiquitin ligase, interacts with caspase-8 death effector domains and ubiquitinates caspase-8 with K63-linked polyubiquitin chains that do not target caspase-8 for degradation but decrease the caspase-8 activation. HECTD3 depletion can sensitize cancer cells to extrinsic apoptotic stimuli. In addition, HECTD3 inhibits TNF-related apoptosis-inducing ligand (TRAIL)-induced caspase-8 cleavage in an E3 ligase activity-dependent manner. Mutation of the caspase-8 ubiquitination site at K215 abolishes the HECTD3 protection from TRAIL-induced cleavage. Finally, HECTD3 is frequently overexpressed in breast carcinomas. These findings suggest that caspase-8 ubiquitination by HECTD3 confers cancer cell survival.",

keywords = "Apoptosis, Breast cancer, Caspase-8, HECTD3, Ubiquitination",

author = "Y. Li and Y. Kong and Z. Zhou and H. Chen and Z. Wang and Hsieh, \{Y. C.\} and D. Zhao and X. Zhi and J. Huang and J. Zhang and H. Li and C. Chen",

note = "Funding Information: Acknowledgements. We thank Dr. Gabriel Nu{\~n}ez from University of Michigan, Dr. James Zhijian Chen from University of Texas, Dr. Chunghong Yan from Albany Medical College, and Dr. Dixit, V. M. from Genentech for reagents. Drs. Gang Liu and Guoning Liao from Albany Medical College provided technical support. This study was supported in part by National Key Basic Research Program of China (No. 2013CB910900), grants from National Nature Science Foundation of China (81120108019, 81072162, and U1132605), and a grant from Yunnan Province High-Profile Scientist Program (2010CI114).",

year = "2013",

month = nov,

doi = "10.1038/cddis.2013.464",

language = "English (US)",

volume = "4",

journal = "Cell Death and Disease",

issn = "2041-4889",

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AU - Li, Y.

AU - Kong, Y.

AU - Zhou, Z.

AU - Chen, H.

AU - Wang, Z.

AU - Hsieh, Y. C.

AU - Zhao, D.

AU - Zhi, X.

AU - Huang, J.

AU - Zhang, J.

AU - Li, H.

AU - Chen, C.

N1 - Funding Information: Acknowledgements. We thank Dr. Gabriel Nuñez from University of Michigan, Dr. James Zhijian Chen from University of Texas, Dr. Chunghong Yan from Albany Medical College, and Dr. Dixit, V. M. from Genentech for reagents. Drs. Gang Liu and Guoning Liao from Albany Medical College provided technical support. This study was supported in part by National Key Basic Research Program of China (No. 2013CB910900), grants from National Nature Science Foundation of China (81120108019, 81072162, and U1132605), and a grant from Yunnan Province High-Profile Scientist Program (2010CI114).

PY - 2013/11

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N2 - Apoptosis resistance is a hurdle for cancer treatment. HECTD3, a new E3 ubiquitin ligase, interacts with caspase-8 death effector domains and ubiquitinates caspase-8 with K63-linked polyubiquitin chains that do not target caspase-8 for degradation but decrease the caspase-8 activation. HECTD3 depletion can sensitize cancer cells to extrinsic apoptotic stimuli. In addition, HECTD3 inhibits TNF-related apoptosis-inducing ligand (TRAIL)-induced caspase-8 cleavage in an E3 ligase activity-dependent manner. Mutation of the caspase-8 ubiquitination site at K215 abolishes the HECTD3 protection from TRAIL-induced cleavage. Finally, HECTD3 is frequently overexpressed in breast carcinomas. These findings suggest that caspase-8 ubiquitination by HECTD3 confers cancer cell survival.

AB - Apoptosis resistance is a hurdle for cancer treatment. HECTD3, a new E3 ubiquitin ligase, interacts with caspase-8 death effector domains and ubiquitinates caspase-8 with K63-linked polyubiquitin chains that do not target caspase-8 for degradation but decrease the caspase-8 activation. HECTD3 depletion can sensitize cancer cells to extrinsic apoptotic stimuli. In addition, HECTD3 inhibits TNF-related apoptosis-inducing ligand (TRAIL)-induced caspase-8 cleavage in an E3 ligase activity-dependent manner. Mutation of the caspase-8 ubiquitination site at K215 abolishes the HECTD3 protection from TRAIL-induced cleavage. Finally, HECTD3 is frequently overexpressed in breast carcinomas. These findings suggest that caspase-8 ubiquitination by HECTD3 confers cancer cell survival.

KW - Apoptosis

KW - Breast cancer

KW - Caspase-8

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KW - Ubiquitination

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The HECTD3 E3 ubiquitin ligase facilitates cancer cell survival by promoting K63-linked polyubiquitination of caspase-8

Abstract

Keywords

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