Frye and Watt have identified a new RNA methyltransferase that is a direct target of MYC and contributes to tumorigenesis. MISU (MYC-induced SUN-domain-containing protein) is overexpressed in many human tumours, and its knockdown decreases proliferation and tumour growth in a xenograft model.

The authors used microarrays to screen RNA isolated from skin cells of mice that express an inducible form of MYC. One mRNA that was strongly induced by MYC encoded an unknown protein, which homology indicated might be an RNA methyltransferase. This activity was confirmed biochemically, and expression studies showed that it is expressed in epidermal cells and other cell types. In G1 phase it is found at low levels, predominantly in the nucleoli, where it interacts with transcripts that have been produced by RNA polymerase III. By contrast, during S phase it is more highly expressed and is more evenly distributed in other parts of the nucleus. Chromatin immunoprecipitation confirmed that MISU is a direct target of MYC.

RNA interference (RNAi) constructs against MISU were expressed in proliferating human keratinocytes. They caused a decrease in proliferation and inhibited MYC-induced differentiation. These effects, and the direct regulation by MYC, led the authors to look for MISU overexpression in tumours. MISU was highly expressed in murine benign epidermal papillomas and malignant squamous-cell carcinomas (SCCs). In humans, 7/7 breast carcinomas, 3/4 colon carcinomas and 2/5 oral SCCs had increased MISU expression, although no such increase was found in rectal cancer. In human SCC cells that were xenografted into mice, RNAi knockdown of MISU reduced tumour size.

MISU might be an important link in understanding MYC-induced tumorigenesis. It also represents a potential target for therapy, as it is only required at low levels in normal cells, and knocking down the levels in tumours to equivalent low levels is sufficient to reduce tumour growth.