USP22 overexpression leads to aberrant signal transduction but is not sufficient to drive tumor formation in mice

USP22 overexpression is observed in several human cancers and is correlated with poor patient outcomes. The molecular basis underlying this correlation is not clear. USP22 is the catalytic subunit of the deubiquitylation module in the SAGA histone modifying complex, which regulates gene transcription. Our previous work demonstrated that loss of USP22 in mice leads to decreased expression of several components of receptor tyrosine kinase and TGFβ signaling pathways. To determine whether these pathways are upregulated when USP22 is overexpressed, we created a mouse model that expresses high levels of USP22 in all tissues. Phenotypic characterization of these mice revealed over branching of the mammary glands in females. Transcriptomic analyses indicate upregulation of key pathways involved in mammary gland branching in mammary epithelial cells derived from the USP22 overexpressing mice, including estrogen receptor, ERK/MAPK and TGFβ signaling. However, USP22 overexpression did not lead to increased tumorigenesis in any tissue. Our findings indicate that elevated levels of USP22 are not sufficient to induce tumors but it may enhance signaling abnormalities associated with oncogenesis. To determine changes in gene expression profile upon Usp22 ubiquitous overexpression in adult nulliparous females, total RNA from mammary gland epithelial cells of seven pairs of littermate – matched 3.5-month wild-type and Rosa26KI-Usp22 OE/OE mice was extracted for deep sequencing. Key genes identified from RNAseq were validated by qRT-PCR using RNA from the same samples that were used for sequencing.