ABSTRACT
Acetylation, a critical regulator of diverse cellular processes, holds significant implications in various cancer contexts. Further understanding of the acetylation patterns of key cancer-driven proteins is crucial for advancing therapeutic strategies in cancer treatment. This study aimed to unravel the acetylation patterns of Engulfment and Cell Motility Protein 1 (ELMO1) and its relevance to the pathogenesis of colorectal cancer (CRC). Immunoprecipitation and mass spectrometry precisely identified lysine residue 505 (K505) as a central acetylation site in ELMO1. P300 emerged as the acetyltransferase for ELMO1 K505 acetylation, while SIRT2 was recognized as the deacetylase. Although K505 acetylation minimally affected ELMO1's localization and stability, it played a crucial role in mediating ELMO1-Dock180 interaction, thereby influencing Rac1 activation. Functionally, ELMO1 K505 acetylation proved to be a pivotal factor in CRC progression, exerting its influence on key cellular processes. Clinical analysis of CRC samples unveiled elevated ELMO1 acetylation in primary tumors, indicating a potential association with CRC pathologies. This work provides insights into ELMO1 acetylation and its significance in advancing potentially therapeutic interventions in CRC treatment.
Subject(s)
Adaptor Proteins, Signal Transducing , Colorectal Neoplasms , rac1 GTP-Binding Protein , Humans , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Colorectal Neoplasms/genetics , Acetylation , rac1 GTP-Binding Protein/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Cell Line, Tumor , Disease Progression , Sirtuin 2/metabolism , Sirtuin 2/genetics , Cell Movement , HCT116 CellsABSTRACT
Objectives: Emerging evidence has demonstrated that tumour budding (TB) is negatively associated with T-lymphocyte infiltration in CRC. Despite extensive research, the molecular characteristics of immunologically 'hot' TB remain poorly understood. Methods: We quantified the number of TB by haematoxylin-eosin (H&E) sections and the densities of CD3+ and CD8+ T-lymphocytes by immunohistochemistry in a CRC cohort of 351 cases who underwent curative resection. We analysed the differential expression and T-lymphocyte infiltration score of 37 human epithelial keratins in CRC using RNA sequencing from the TCGA dataset. In 278 TB-positive cases, KRT17 expression was evaluated in tumour centre (TC) and TB with a staining score. Patient demographic, clinicopathological features and survival rates were analysed. Results: In a CRC cohort of 351 cases, low-grade TB was associated with high CD3+ and CD8+ T-cell densities in the invasive margin (IM) but not in the TC. Of 37 human epithelial keratins, only KRT17 expression in TB had an apparent association with TB-grade and T-lymphocyte infiltration. In 278 TB-positive cases, high KRT17 expression in TB (KRT17TB) was negatively associated with low-grade TB and positively associated with high CD3+ and CD8+ T-cell densities in IM. High KRT17TB predicted early tumour grade, absence of lymph node metastasis and absence of tumour deposits. Additionally, patients with high KRT17TB had good overall survival and disease-free survival. Notably, low KRT17TB can specifically identify those patients with a poor prognosis among colorectal cancer patients with low TB and high T-lymphocyte infiltration. Conclusions: KRT17 can be employed as a new indicator for distinguishing different immunological TBs.