Stabilization of MCL-1 by E3 ligase TRAF4 confers radioresistance.
Ming LiFeng GaoXiaoying LiYu GanShuangze HanXinfang YuHaidan LiuWei LiPublished in: Cell death & disease (2022)
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.
Keyphrases
- cell proliferation
- signaling pathway
- poor prognosis
- acute myeloid leukemia
- gene expression
- acute lymphoblastic leukemia
- dna damage response
- long non coding rna
- endothelial cells
- bone marrow
- diffuse large b cell lymphoma
- cell cycle
- multiple myeloma
- pi k akt
- hodgkin lymphoma
- cell therapy
- oxidative stress
- high glucose
- protein kinase
- diabetic rats
- induced pluripotent stem cells
- endoplasmic reticulum stress
- smoking cessation
- functional connectivity
- dna repair