胰腺神经内分泌瘤（PanNETs）是胰腺中一组罕见而散发性的恶性肿瘤。MEN1基因是PanNETs中最常发生的变异基因。MEN1编码的蛋白是一种典型的抑癌基因，其与表观遗传和转录因子形成复合物，并且是治疗PanNET患者的一个有吸引力的靶点。进一步了解MEN1蛋白在PanNETs中的调节机制，可以确定针对MEN1的治疗策略。在这里，我们发现neddylation途径和DCAF7介导的泛素化是MEN1蛋白表达的调控机制。与对照组相比，PanNET组织中neddylation途径和DCAF7的成员表达显著增加，并与PanNET患者的预后不良有关。使用neddylation抑制剂MLN4924或RNA干扰抑制neddylation明显诱导MEN1积累，抑制癌相关恶性表型。通过结合和催化其泛素化，CUL4B和DCAF7促进MEN1的降解。在对依托利珠单抗（一种广泛用于治疗晚期PanNET患者的药物mTOR抑制剂）有耐受性的PanNET细胞中，降低DCAF7表达能克服耐受性，并协同依托利珠单抗抑制mTOR活性并抑制癌细胞生长。在体内外同时靶向MEN1可逆转DCAF7损失的影响。 DCAF7和MEN1之间的负相关在临床样本中得到了进一步验证。本研究揭示了neddylation和CUL4B-DCAF7轴介导的胰腺神经内分泌瘤中MEN1表达的后转录调控，并确定了治疗MEN1相关PanNET患者的潜在治疗靶点。

Pancreatic neuroendocrine tumors (PanNETs) are a group of rare sporadic malignant tumors in the pancreas. MEN1 is the most frequently mutated gene in PanNETs. The MEN1-encoded protein is a typical tumor suppressor that forms a complex with epigenetic and transcription factors and is an attractive target for therapeutic interventions for PanNET patients. A better understanding of the regulation of MEN1 protein expression in PanNETs could identify strategies for targeting MEN1. Here, we found that the neddylation pathway and DCAF7-mediated ubiquitination regulated MEN1 protein expression. Increased expression of members of the neddylation pathway and DCAF7 were found in PanNET tissues compared to paired-adjacent tissues and were associated with poor prognosis in PanNET patients. Suppression of neddylation using the neddylation inhibitor MLN4924 or RNA interference significantly induced MEN1 accumulation and repressed cancer-related malignant phenotypes. CUL4B and DCAF7 promoted MEN1 degradation by binding and catalyzing its ubiquitination. In PanNET cells resistant to everolimus, a pharmacological mTOR inhibitor widely used for advanced PanNET patient treatment, the downregulation of DCAF7 expression overcame resistance and synergized with everolimus to suppress mTOR activation and inhibit cancer cell growth. The effects of DCAF7 loss could be counteracted by the simultaneous knockdown of MEN1 both in vitro and in vivo. The inverse correlation between DCAF7 and MEN1 was further validated in clinical specimens. This study revealed that the posttranslational control of MEN1 expression in PanNET is mediated by neddylation and the CUL4B-DCAF7 axis and identifies potential therapeutic targets in MEN1-associated PanNET patients.