LAUSR

Introduction Cancer therapy is limited by lack of specificity. Thus, identifying molecules that are relevant for tumorigenesis and selectively expressed by cancer cells is of paramount medical importance. Here, following computational and immunohistological analyses, we found in both mouse and human that FKBP10 is an oncofetal protein that during adulthood is selectively expressed in lung cancer cells. Our results from in vitro and in vivo functional assays demonstrated that FKBP10 downregulation hinders growth of lung cancer cells and tumours owing to decreased cell proliferation. By performing proteomic analysis, we identified several members involved in protein translation as putative FKBP10 binding partners. Ribosomal profiling results indicated that FKBP10 downregulation reduces formation of ribosomal polysomes while translation initiation remains unaffected. Thus, we uncovered FKBP10 as a specific requirement of lung tumorigenesis with a role in protein translation elongation that can be exploited for therapeutic gain. Material and methods 2 mouse model Immunoblotting and immunoprecipitation. shRNAs, Virus production and transduction; Measurement of 35S-labelled methionine incorporation in cells; Ribosomal profiling; CT-scan imaging. Results and discussions In this study, we found that FKBP10 is specifically expressed in lung tumours in mice and humans while not expressed in healthy tissues. Importantly, our data show that FKBP10 depletion hinders cancer proliferation both in vitro in human lung cancer-derived cells and in vivo in two lung cancer mouse model. The relevance of this finding is bolstered by an association analysis indicating that FKBP10 expression negatively correlates with survival of patients with lung adenocarcinoma. Here, we found that FKBP10 is present at translating ribosomes and sustains protein translation elongation and protein synthesis in lung cancer cells bearing oncogenic KRAS mutation. Importantly, FKBP10 depletion hinders proliferation of cancer cells. Thus, our results support the notion that FKBP10 is an adaptive mechanism required for the increased protein synthesis demand in proliferating lung cancer cells. Conclusion In summary, we uncovered FKBP10 as a oncofetal protein specifically expressed in KRAS-driven lung tumours. Depletion of FKBP10 hinders tumour proliferation by a mechanisms involving suppression of protein translation elongation. Finally, we propose that inhibition of FKBP10 could be exploited for therapeutic purpouses against lung cancer and perhaps other types of malignancies.