Direct in vivo RNAi screen unveils myosin IIa as a tumor suppressor of squamous cell carcinomas.

Publication Type:

Journal Article

Source:

Science (New York, N.Y.), Volume 343, Issue 6168, p.309-13 (2014)

Keywords:

2014, Animals, Carcinoma, Squamous Cell, Center-Authored Paper, Genetic Testing, Head and Neck Neoplasms, Human Biology Division, Humans, Lung Neoplasms, MICE, Mice, Knockout, Molecular Motor Proteins, Mutation, Myosin Heavy Chains, Nonmuscle Myosin Type IIA, RNA Interference, Transcription, Genetic, Tumor Suppressor Protein p53, Tumor Suppressor Proteins

Abstract:

Mining modern genomics for cancer therapies is predicated on weeding out "bystander" alterations (nonconsequential mutations) and identifying "driver" mutations responsible for tumorigenesis and/or metastasis. We used a direct in vivo RNA interference (RNAi) strategy to screen for genes that upon repression predispose mice to squamous cell carcinomas (SCCs). Seven of our top hits-including Myh9, which encodes nonmuscle myosin IIa-have not been linked to tumor development, yet tissue-specific Myh9 RNAi and Myh9 knockout trigger invasive SCC formation on tumor-susceptible backgrounds. In human and mouse keratinocytes, myosin IIa's function is manifested not only in conventional actin-related processes but also in regulating posttranscriptional p53 stabilization. Myosin IIa is diminished in human SCCs with poor survival, which suggests that in vivo RNAi technology might be useful for identifying potent but low-penetrance tumor suppressors.