註釋 The retinoblastoma tumor suppressor RB is a central cell cycle regulator. Here we demonstrate that RB can be methylated by SMYD2 at lysine 860, a highly conserved and novel site of modification. This methylation event occurs in vitro and in cells and is regulated during cell cycle progression, cellular differentiation, and in response to DNA damage. Furthermore, we show that RB mono-methylation at lysine 860 provides a direct binding site for the methyl-binding domain of the transcriptional repressor L3MBTL1. This modification may be crucial for regulating the function of RB as a tumor suppressor. Inactivation of RB and activation of the MYC family of oncogenes are frequent events in a large spectrum of human cancers. Here, we sought to also test whether loss of RB function would affect cancer development in a mouse model of c-MYC-induced hepatocellular carcinoma (HCC). We found that RB inactivation has minimal effects on the cell cycle, cell death, and differentiation features of liver tumors driven by increased levels of c-MYC. However, combined loss of RB and activation of c-MYC led to an increase in polyploidy in mature hepatocytes before the development of tumors and a trend for decreased survival after cancer initiation. 