講演情報
[BP-4]ユビキチンE3リガーゼ基質アダプターLZTR1はRASプロテオスタシスと腫瘍増殖を制御する
○阿部 太紀, 森崎 佳歩, 新堀 哲也, 青木 洋子 (東北大学 大学院医学系研究科 遺伝医療学分野)
※12月15日（木）と16日（金）で同一演題の発表を行います。
Background: Leucine zipper-like transcriptional regulator 1 (LZTR1) is a substrate adaptor of CUL3-based E3 ubiquitin ligase. Mutations in LZTR1 have been identified in patients with Noonan syndrome and several cancers. However, the functional role of LZTR1 is not fully understood. Results: First, we explored the substrates of LZTR1 and identified RAS family GTPases, including classical RAS, MRAS, and RIT1. LZTR1 overexpression could promote polyubiquitination and degradation of RAS, whereas LZTR1 knockdown caused increased expression of RAS and phospho-ERK1/2. We then established LZTR1-knockout lung carcinoma cells (A549-KO), which showed high proliferative and invasive activity compared to parental cells. In xenograft tumor models, deficiency of LZTR1 increased tumor growth and RAS expression. Multi-omics analysis to clarify the pathways related to tumor growth in LZTR1 knockout cells showed that MAPK signaling and epithelial-mesenchymal transition (EMT) were significantly enriched features. Indeed, the expression of EMT marker genes, including SLUG, was significantly increased in TGF-β1-treated A549-KO cells compared to parental cells. Finally, the increased expression was suppressed by the knockdown of RREB1, a regulator of RAS/MAPK signaling dependent EMT. Discussion and Conclusion: We showed that deficiency of LZTR1, a RAS killer protein, could promote tumor growth by increasing sensitivity to EMT through RAS-MAPK-RREB1 pathway. Our results provide a clue to the mechanism of carcinogenesis caused by LZTR1 deficiency.