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.

中文翻译：

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MAP3K11促进自噬活性并与口腔鳞状细胞癌的恶性程度相关

自噬相关 4B (ATG4B) 是自噬核心机制所需的蛋白酶。ATG4B 的磷酸化促进自噬并与癌症的不良结果相关。然而，关于 ATG4B 磷酸化的上游激酶及其与癌症患者临床结果的关联知之甚少。通过 siRNA 文库筛选，MAP3K11 被确定为磷酸化 ATG4B 并增加其蛋白水解活性的潜在激酶。MAP3K11 的消融减弱了口腔癌细胞中的 pS383/392-ATG4B 蛋白水平和自噬通量。此外，MAP3K11 的缺失会抑制口腔癌细胞的生长、迁移/侵袭，并协同饥饿降低细胞活力。MAP3K11 敲除癌细胞在体内也显示出生长抑制。此外，MAP3K11在口腔鳞状细胞癌（OSCC）患者肿瘤组织中的蛋白水平高于癌旁正常组织，其中口腔鳞状细胞癌（BMSCC）179例，舌鳞状细胞癌（TSCC）249例。MAP3K11 蛋白水平与 OSCC 患者的 ATG4B 和 pS383/392-ATG4B 水平呈正相关，尤其是在 TSCC 患者中。此外，MAP3K11 和 ATG4B 的高共表达与 BMSCC 和 TSCC 中较差的疾病特异性生存相关，而 MAP3K11 和 pS383/392-ATG4B 的高共表达与 BMSCC 和 TSCC 中不利的无病生存相关。总之，我们的结果表明 MAP3K11 刺激了 ATG4B 的活性和自噬，这可能导致癌细胞的恶性肿瘤。