LAUSR

Proteins containing a CAAX motif at the C-terminus can occur prenylation modification and regulate the localization and activity of a series of key regulatory proteins, including RAS superfamily members, heterotrimeric G proteins, nuclear lamina protein, and several protein kinases and phosphatases. However, studies of prenylated proteins in esophageal cancer are limited. Here, we found that paralemmin-2 (PALM2), a potential prenylated protein, was up-regulated and associated with a poor prognosis of patients, through research on large-scale proteomic data of esophageal cancer in our laboratory. The low throughput verification also showed that the expression of PALM2 in esophageal cancer tissues was higher than that in their paired normal esophageal epithelial tissues, and it was generally expressed in the membrane and cytoplasm of esophageal squamous cancer cells (ESCC). PALM2 interacted with the two subunits of farnesyl transferase (FTase), FNTA and FNTB. The FTase inhibitor weakened the membranous location of PALM2 and mutation in the CAAX motif of PALM2 (PALM2C408S) impaired its membranous localization, indicating PALM was prenylated by FTase. Overexpressed PALM2 promoted the migration of cancer cells, whereas PALM2C408S lost this ability. Mechanistically, PALM2 interacted with the N-terminal FERM domain of ezrin of Ezrin/Radixin/Moesin (ERM) family dependent on its prenylation. The mutagenesis indicated that lysine residues K253/K254/K262/K263 in ezrin’s FERM domain and cysteine residue C408 in PALM2’s CAAX motif were important for their interaction and ezrin activation. The knockout of ezrin prevented enhanced cancer cell migration by PALM2 overexpression. PALM2, depending on its prenylation, made ezrin get more membranous distribution and increased the phosphorylation of ezrin Y146 site. In summary, prenylated PALM2 promoted the migration of cancer cells through activating ezrin. (This work was supported by the National Natural Science Foundation of China (82173034, 81172264), and Innovative Team Grant of Guangdong Department of Education (2021KCXTD005)). Citation Format: Danxia Deng, Chengyu Li, Zhenyuan Zheng, Bing Wen, Liandi Liao, Enmin Li, Liyan Xu. Prenylated PALM2 promotes the migration of esophageal squamous cancer cells through activating ezrin. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3610.