“Smurf”-ing tumors on the chromatin through RNF20

Abstract

In the modern mythology of Dutch comic world, Smurfs are little blue creatures who say “smurf” for anything they do. In the parlance of molecular biology, there live two Smurfs so named because they are Smad ubiquitination regulator factor 1 and 2. Just like those blue devils on the television, the molecular Smurfs are also versatile; capable of controlling bone development, actin cytoskeleton dynamics, cellular senescence, and planar cell polarity in addition to their prototypic function in transforming growth factor β (TGF-β) signaling. Now, the realm of Smurf influence has expanded even further to epigenetic modifications of histones governing the chromatin landscape. A recent study from Ying E. Zhang’s group in the National Cancer Institute of NIH published in Nature Medicine shows that Smurf2 regulates ubiquitin modification of histone H2B and trimethylation of histone H3 through targeting RNF20, the major H2B ubiquitin ligase. The importance of this regulation is underscored by the fact that genomic ablation of Smurf2 causes a loosening of chromatin compaction and over the long run leads to genomic instability and a disposition to a wide spectrum of tumors in aged mice. This novel cancer-causing mechanism has human relevance as well, since the study reports an inverse relationship between loss of Smurf2 function and up-regulation of RNF20 in many types of human cancers. Smurf1 and 2 were initially characterized as key regulators in TGF-β and bone morphogenetic protein (BMP) signaling pathways, in which they function as ubiquitin E3 ligases by targeting Smad proteins and the TGF-β type I receptor for protesomal degradation. Due to the similarity in their protein sequences, Smurf1 and Smurf2 were thought to have overlapping functions. Indeed, mice with single knockout of Smurf1 (Smurf1) or Smurf2 (Smurf2) are viable, fertile and display no overt developmental phenotypes; nevertheless, double knockout of Smurf1 and Smurf2 simultaneously causes embryonic lethality, most likely due to defects in planar cell polarity (Narimatsu et al., 2009), indicating that Smurf proteins have an essential common function during embryonic development. Despite the lack of an embryonic defect, both Smurf1 and Smurf2 single knockout mice developed distinct phenotypes as they aged, suggesting that Smurf1 or Smurf2 each has unique targets (Yamashita et al., 2005). The Zhang group showed previously that aged Smurf1 mice accumulated a greater amount of bone mass than control littermates due to the increased activity of osteoblasts. The target of this osteogenic role of Smurf1 has been determined to be MEKK2. In the current study from the same group, Blank and colleagues report that aged Smurf2 mice developed a wide spectrum of tumors. Several earlier studies have suggested that Smurf2 may have a role in tumorigenesis; these include demonstration of elevated Smurf2 expression in breast cancers correlating with tumor progression by modulating TGF-β signaling (Fukuchi et al., 2002; Jin et al., 2009), and induction of senescence by Smurf2 leading to growth inhibition in certain cancer cell lines (Zhang et al., 2008). However, the current study from the Zhang group unequivocally demonstrated the tumor suppressor function of Smurf2 and determined the molecular mechanism. The story began when Blank and colleagues used the genetic approach to delete the Smurf2 alleles in mice in an attempt to investigate the physiological function of Smurf2. They found that loss of Smurf2 causes a higher tumor incidence as the knockout mice aged. Surprisingly, a wide range of tumor types were revealed in different organs in Smurf2 mice, suggesting that Smurf2 plays a central role in controlling tumor formation instead of targeting a specific pathway in a particular organ. To elucidate the mechanism of Smurf2’s role in tumorigenicity, Blank and colleagues characterized mouse embryonic fibroblast (MEF) cells isolated from Smurf2 embryos and showed that Smurf2 cells gain growth advantage and undergo oncogenic transformation in late passages. Interestingly, restoration of Smurf2 does not inhibit cell proliferation in late-passage Smurf2 cells, suggesting that loss of Smurf2 causes a chronic effect rather than an acute response in cell growth