LATS1/2 Loss Promote Tumor Immune Evasion in Endometrial Cancer through Downregulating MHC-I Expression
LATS1/2 is frequently mutated and down-regulated in endometrial cancer (EC), but the contribution of LATS1/2 to endometrial tumor progression remains unclear. Here, we discovered an unexpected role of LATS1/2 in regulating MHC class I expression in EC. We demonstrate that the knockout of LATS1/2 in EC cells resulted in significant down-regulation of multiple genes of MHC/HLA Class I family and leaded to insensitivity to tumor immunotherapy. Furthermore, we found that the regulation of LATS1/2 on MHC/HLA expression does not depend on the classical Hippo pathway but on their direct interaction with STAT1 to phosphorylate STAT1 to promote STAT1 accumulating and moving into the nucleus to enhance the transcriptional activation of IRF1/NLRC5 on MHC-I. The kinase-dead mutant LATS1/2 attenuates STAT1 phosphorylation at Ser727. The expressions of LATS1/2, MHC-I, CD8A and p-STAT1(S727)are positive correlation in tissues of EC confirming our findings furtherly. Furthermore, LATS1/2 expression was negatively correlated with tumor stage in EC tissues. These findings reveal novel molecular mechanisms underlying tumor immunogenicity deficiency and elucidate the potential immunotherapy biomarker targeting LATS1/2 in EC. Overall design: To study the biological function of LATS1/2 in EC, we generated LATS1/2 double knockout (dKO) cell lines using CRISPR/Cas9 methods. We then performed gene expression profiling analysis using data obtained from RNA-seq of 2 different cells. Comparative gene expression profiling analysis of RNA-seq data for KLE cells and its LATS1/2-dKO derivatives.