TRAF6 Restricts p53 Mitochondrial Translocation, Apoptosis, and Tumor Suppression.
Mitochondrial p53 is involved in apoptosis and tumor suppression. However, its regulation is not well studied. Here, we show that TRAF6 E3 ligase is a crucial factor to restrict mitochondrial translocation of p53 and spontaneous apoptosis by promoting K63-linked ubiquitination of p53 at K24 in cytosol, and such ubiquitination limits the interaction between p53 and MCL-1/BAK. Genotoxic stress reduces this ubiquitination in cytosol by S13/T330 phosphorylation-dependent translocation of TRAF6 from cytosol to nucleus, where TRAF6 also facilitates the K63-linked ubiquitination of nuclear p53 and its transactivation by recruiting p300 for p53 acetylation. Functionally, K63-linked ubiquitination of p53 compromised p53-mediated apoptosis and tumor suppression. Colorectal cancer samples with WT p53 reveal that TRAF6 overexpression negatively correlates with apoptosis and predicts poor response to chemotherapy and radiotherapy. Together, our study identifies TRAF6 as a critical gatekeeper to restrict p53 mitochondrial translocation, and such mechanism may contribute to tumor development and drug resistance.
Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
Xian
X
Zhang
National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan; Department of Pathology, Chi-Mei Foundational Medical Center, Tainan 710, Taiwan.
Chien-Feng
CF
Li
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, 1#, Yixueyuan Road, Chongqing, 400016, China.
Ling
L
Zhang
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi 613, Taiwan.
Ching-Yuan
CY
Wu
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
Lixia
L
Han
Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Guoxiang
G
Jin
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Abdol Hossein
AH
Rezaeian
Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
Fei
F
Han
Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Chunfang
C
Liu
Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Chuan
C
Xu
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Xiaohong
X
Xu
Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 41354, Taiwan.
Chih-Yang
CY
Huang
College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan; Department of Medical Genetics, Pediatrics, and Medical Research, China Medical University Hospital, Taichung 40402, Taiwan.
Fuu-Jen
FJ
Tsai
Department of Biotechnology, Asia University, Taichung 41354, Taiwan; Center of Molecular Medicine, China Medical University Hospital, Taichung 40402, Taiwan.
Chang-Hai
CH
Tsai
Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Kounosuke
K
Watabe
Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 41354, Taiwan. Electronic address: hulin@wakehealth.edu.
Hui-Kuan
HK
Lin
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D021381:Protein Transport; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D016019:Survival Analysis; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism
C545747:2-phenylacetylenesulfonamide; D000970:Antineoplastic Agents; C494772:BAK1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D013449:Sulfonamides; D048029:TNF Receptor-Associated Factor 6; C000604754:Tifab protein, human; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D008239:Lysine
K63-linked ubiquitination of p53; MCL1/BaK; TRAF6 inhibits apoptosis; colorectal cancer; genotoxic stress; p300 recruitment; p53 K24 ubiquitination; p53 mitochondrial translocation; p53 transactivation; tumor suppression