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Author Spotlight: A Selective Luciferase-Based Assay for Monitoring ATG4B 27 Activity in Cells
Published on: June 30, 2023
MAP3K11 facilitates autophagy activity and is correlated with malignancy of oral squamous cell carcinoma
Pei-Feng Liu1,2,3, Chun-Feng Chen4,5, Luo-Ping Ger6
1Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.
Abstract:
Autophagy-related 4B (ATG4B) is a protease required for core machinery of autophagy. Phosphorylation of ATG4B promotes autophagy and is correlated with poor outcome of cancer. However, little is known about the upstream kinases for ATG4B phosphorylation and their association with clinical outcomes of cancer patients. Through siRNA library screening, MAP3K11 was identified as a potential kinase that phosphorylates ATG4B and increases its proteolytic activity. Ablation of MAP3K11 attenuated pS383/392-ATG4B protein levels and autophagic flux in oral cancer cells. Moreover, loss of MAP3K11 inhibited oral cancer cell growth, migration/invasion, and synergized starvation-reduced cell viability. MAP3K11 knock-out cancer cells also showed growth inhibition in vivo. Furthermore, the protein level of MAP3K11 was higher in tumor tissues than that in adjacent normal tissues in patients with oral squamous cell carcinoma (OSCC), comprising 179 buccal mucosa squamous cell carcinoma (BMSCC) and 249 tongue squamous cell carcinoma (TSCC). MAP3K11 protein levels were positively correlated with ATG4B and pS383/392-ATG4B levels in patients with OSCC, particularly in TSCC. In addition, high coexpression of MAP3K11 and ATG4B was associated with poor disease-specific survival in BMSCC and TSCC, while high coexpression of MAP3K11 and pS383/392-ATG4B was associated with unfavorable disease-free survival in BMSCC and TSCC. Taken together, our results indicated that MAP3K11 stimulated activity of ATG4B and autophagy, which may confer to malignancy of cancer cells. The expression of MAP3K11 and ATG4B was further associated with poor survival of OSCC, suggesting MAP3K11 could serve as a theranostic target of patients with OSCC.
Insights
Mitogen-activated protein kinase kinase kinase 11 (MAP3K11) phosphorylates Autophagy-related 4B (ATG4B), promoting autophagy and oral cancer progression. MAP3K11 and ATG4B expression correlate with poor survival in oral squamous cell carcinoma patients.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Autophagy-related 4B (ATG4B) is crucial for autophagy, and its phosphorylation correlates with poor cancer prognosis.
- The upstream kinases regulating ATG4B phosphorylation and their clinical relevance remain largely unknown.
Purpose of the Study:
- To identify kinases phosphorylating ATG4B and investigate their role in oral cancer.
- To explore the clinical significance of MAP3K11 and ATG4B in oral squamous cell carcinoma (OSCC).
Main Methods:
- siRNA library screening to identify ATG4B-phosphorylating kinases.
- In vitro assays using oral cancer cells to assess MAP3K11's effect on ATG4B, autophagy, and cell behavior.
- In vivo studies using xenograft models.
- Analysis of MAP3K11 and ATG4B protein levels in patient tumor tissues (OSCC, BMSCC, TSCC).
Main Results:
- MAP3K11 was identified as a kinase that phosphorylates ATG4B, enhancing its activity and autophagic flux.
- MAP3K11 ablation inhibited oral cancer cell growth, migration, invasion, and in vivo tumor growth.
- Elevated MAP3K11 levels were observed in OSCC tissues and correlated positively with ATG4B and phosphorylated ATG4B.
- High coexpression of MAP3K11 and ATG4B was linked to poor survival in OSCC patients.
Conclusions:
- MAP3K11 promotes oral cancer malignancy by activating ATG4B and enhancing autophagy.
- MAP3K11 expression is associated with poor patient survival in OSCC.
- MAP3K11 represents a potential theranostic target for oral squamous cell carcinoma.
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