类似亮氨酸拉链转录调节蛋白1（LZTR1）是Cullin 3（CUL3）基于E3泛素连接酶的底物适配剂，可调节RAS亚家族的蛋白质稳态。在多种类型的癌症患者中已鉴定出LZTR1的突变。然而，除RAS亚家族之外，LZTR1在肿瘤转移中的作用以及LZTR1的靶分子目前还不明确。在这里，我们展示了LZTR1缺失增加肿瘤生长和转移的现象。在肺腺癌细胞中，LZTR1缺失导致RAS亚家族的堆积，增强了细胞增殖、侵袭和异种移植瘤生长。为了阐明与肿瘤进展相关的途径，我们进行了多组学分析，结果显示MAPK信号传导、上皮间质转化（EMT）和细胞外基质（ECM）重塑相关的基因本体术语在LZTR1敲除细胞中富集。确实，LZTR1缺失在TGF-β1处理下诱导了EMT标记物的高表达。我们通过搜索与LZTR1相互作用的新的底物，发现了一个参与胶原分泌的Kelch-like蛋白12（KLHL12）。LZTR1能够抑制KLHL12介导的SEC31A泛素化，而LZTR1缺失促进了胶原分泌。LZTR1-RIT1和LZTR1-KLHL12在分子相互作用方面是独立的，它们之间不直接干涉。此外，我们发现LZTR1缺失显著增加了肺转移并促进转移性肿瘤周围的ECM沉积。由于富含胶原的细胞外基质作为迁移途径并促进转移，RAS的增加表达和胶原沉积可能具有协同或加成的作用，导致肿瘤进展和转移。总之，LZTR1缺失通过增强对EMT诱导的敏感性和促进胶原分泌而表现出高转移潜能。LZTR1对KLHL12的功能抑制提供了重要依据，表明LZTR1可能是BTB-Kelch家族成员的抑制因子。这些结果为LZTR1缺失致癌机制提供了线索。 © 2023. 作者（们）。

Leucine zipper-like transcriptional regulator 1 (LZTR1), a substrate adaptor of Cullin 3 (CUL3)-based E3 ubiquitin ligase, regulates proteostasis of the RAS subfamily. Mutations in LZTR1 have been identified in patients with several types of cancer. However, the role of LZTR1 in tumor metastasis and the target molecules of LZTR1, excluding the RAS subfamily, are not clearly understood. Here, we show that LZTR1 deficiency increases tumor growth and metastasis. In lung adenocarcinoma cells, LZTR1 deficiency induced the accumulation of the RAS subfamily and enhanced cell proliferation, invasion, and xenograft tumor growth. Multi-omics analysis to clarify the pathways related to tumor progression showed that MAPK signaling, epithelial-mesenchymal transition (EMT), and extracellular matrix (ECM) remodeling-related gene ontology terms were enriched in LZTR1 knockout cells. Indeed, LZTR1 deficiency induced high expression of EMT markers under TGF-β1 treatment. Our search for novel substrates that interact with LZTR1 resulted in the discovery of a Kelch-like protein 12 (KLHL12), which is involved in collagen secretion. LZTR1 could inhibit KLHL12-mediated ubiquitination of SEC31A, a component of coat protein complex II (COPII), whereas LZTR1 deficiency promoted collagen secretion. LZTR1-RIT1 and LZTR1-KLHL12 worked independently regarding molecular interactions and did not directly interfere with each other. Further, we found that LZTR1 deficiency significantly increases lung metastasis and promotes ECM deposition around metastatic tumors. Since collagen-rich extracellular matrix act as pathways for migration and facilitate metastasis, increased expression of RAS and collagen deposition may exert synergistic or additive effects leading to tumor progression and metastasis. In conclusion, LZTR1 deficiency exerts high metastatic potential by enhancing sensitivity to EMT induction and promoting collagen secretion. The functional inhibition of KLHL12 by LZTR1 provides important evidence that LZTR1 may be a repressor of BTB-Kelch family members. These results provide clues to the mechanism of LZTR1-deficiency carcinogenesis.© 2023. The Author(s).