DNAJA4, DNAJB11 and DNAJC10 induce cell transformation by inhibiting p53 and oncogene-induced senescence.

Objective: Transformation from normal cells to malignant cells is the basis for tumorigenesis. While this cell transformation is known to result from aberrant activation or inactivation of associated genes, these genes have not yet been fully identified. In addition, DNAJs, proteins with a J domain, are known to be molecular co-chaperones, but their cellular functions remain largely unexplored. In this context, we here identified DNAJA4, DNAJB11, and DNAJC10 as pro-transforming genes and elucidated their action mechanisms. Methods: Senescence-associated (SA)-β-galactosidase staining and western blotting were used to analyze cellular senescence and protein expression. Soft agar assay was used to analyze cell transformation. RNA sequencing data was downloaded from the Cancer Genome Atlas (TCGA) database. Results: We observed that overexpression of the three DNAJs inhibited oncogene-induced senescence (OIS) and the p53/p21WAF1/CIP1 pathway under H-RASV12 expression in normal mouse embryonic fibroblasts (MEFs). Additionally, their overexpression inhibited p53-induced senescence. Moreover, overexpression of the three DNAJs induced neoplastic transformation in MEFs under H-RASV12 expression. Furthermore, RNA sequencing analysis showed that the three DNAJs are frequently overexpressed in cancer tissues compared to their matched normal tissues in various human cancers. Conclusion: These results suggest that the three DNAJs are pro-transforming genes whose aberrant overexpression contributes to cell transformation. These results also suggest that the three DNAJs induce cell transformation by inhibiting the senescence function of p53 and OIS. This study may contribute to understanding the molecular basis of cell transformation and the cellular functions of the three DNAJs. [ABSTRACT FROM AUTHOR]