The deubiquitinase USP16 functions as an oncogenic factor in K-RAS-driven lung tumorigenesis

K-RAS mutation and molecular alterations of its surrogates function essentially in lung tumorigenesis and malignant progression. However, it remains elusive how tumor-promoting and deleterious events downstream of K-RAS signaling are coordinated in lung tumorigenesis. Here, we show that USP16, a deubiquitinase involved in various biological processes, functions as a promoter for the development of K-RAS-driven lung tumor. Usp16 deletion significantly attenuates K-ras^G12D-mutation-induced lung tumorigenesis in mice. USP16 upregulation upon RAS activation averts reactive oxygen species (ROS)-induced p38 activation that would otherwise detrimentally influence the survival and proliferation of tumor cells. In addition, USP16 interacts with and deubiquitinates JAK1, and thereby promoting lung tumor growth by augmenting JAK1 signaling. Therefore, our results reveal that USP16 functions critically in the K-RAS-driven lung tumorigenesis through modulating the strength of p38 and JAK1 signaling.