Endogenous LKB1 knockdown accelerates G(1)/S transition through p53 and p16 pathways.

The tumor suppressor LKB1 is inactivated in 90% of Peutz-Jeghers cancer syndrome, 30-40% of non-small cell lung carcinoma, and a variety of other cancers, indicating the loss of LKB1 activity is a critical step in oncogenesis. However, current understanding of LKB1 function is largely limited to the results from cancer cells, and how LKB1 inactivation initiates malignant transformation in normal cells remains unclear. Here we ablated endogenous expression of LKB1 in two normal cell lines: human embryonic kidney 293T cells (HEK-293T cells) and human umbilical vein endothelial cells (HUVECs) by LKB1-specific short hairpin RNAs. Downregulation of endogenous LKB1 lead to a facilitated G(1)/S transition, accompanied by a concomitant increase in Rb phosphorylation (Ser(807/811)). Furthermore, reduced expression of p53 and p16 was observed in LKB1 ablated cells, while no differences were detected for cyclin D1 and cyclin E. These results jointly suggest that endogenous LKB1 knockdown accelerates cell cycle progression through G(1)/S checkpoint in HEK-293T cells and HUVECs, which is at least in part, mediated by decline of p53 and p16 pathways. Our findings provided a plausible mechanism by which loss of LKB1 expression in normal cells contributes to the formation of malignancies.