Stabilization of MCL-1 by E3 ligase TRAF4 confers radioresistance.

Abstract

The E3 ligase TNF receptor-associated factor 4 (TRAF4) is frequently overexpressed and closely related to poor prognosis in human malignancies. However, its effect on carcinogenesis and radiosensitivity in oral squamous cell carcinoma (OSCC) remains unclear. The present study found that TRAF4 was significantly upregulated in primary and relapsed OSCC tumor tissues. Depletion of TRAF4 markedly improved the sensitivity of OSCC cells to irradiation (IR) treatment, showing that tumor cell proliferation, colony formation and xenograft tumor growth were reduced. Mechanistically, IR promoted the interaction between TRAF4 and Akt to induce Akt K63-mediated ubiquitination and activation. TRAF4 knockout inhibited the phosphorylation of Akt and upregulated GSK3β activity, resulting in increased myeloid cell leukemia-1 (MCL-1) S159 phosphorylation, which disrupted the interaction of MCL-1 with Josephin domain containing 1 (JOSD1), and ultimately induced MCL-1 ubiquitination and degradation. Moreover, TRAF4 was positively correlated with MCL-1 in primary and in radiotherapy-treated, relapsed tumor tissues. An MCL-1 inhibitor overcame radioresistance in vitro and in vivo. Altogether, the present findings suggest that TRAF4 confers radioresistance in OSCC by stabilizing MCL-1 through Akt signaling, and that targeting TRAF4 may be a promising therapeutic strategy to overcome radioresistance in OSCC.

• Authors: Ming Li, Feng Gao, Xiaoying Li, Yu Gan, Shuangze Han, Xinfang Yu, Haidan Liu, Wei Li
• Journal: Cell death & disease (Cell Death Dis) Vol. 13 Issue 12 Pg. 1053 (12 19 2022) ISSN: 2041-4889 [Electronic] England
• PMID: 36535926 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-akt
• TNF Receptor-Associated Factor 4
• TRAF4 protein, human
• Ubiquitin-Protein Ligases
• MCL1 protein, human

Topics

• Humans
• Cell Line, Tumor
• Mouth Neoplasms (genetics, radiotherapy)
• Myeloid Cell Leukemia Sequence 1 Protein (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Squamous Cell Carcinoma of Head and Neck (genetics, radiotherapy)
• TNF Receptor-Associated Factor 4 (metabolism)
• Ubiquitin-Protein Ligases (metabolism)
• Radiation Tolerance