Since the advent of rapid and affordable genome sequencing, a myriad of genes has been identified as recurrently altered in cancer. The functions of many of these genes in normal cells and in cancer are still poorly understood, with researchers typically focusing on genes and pathways that are already well established in cancer development like p53, Myc and Ras.
A recent paper from the Vasioukhin lab in Nature Communications seeks to establish how ERG, a relatively understudied oncogene that is mutated in around half of all prostate cancers, contributes to the development of cancer. ERG (ETS-related gene) is a member of the E-26 transformation specific (ETS) family of transcription factors that was first identified in colorectal cancer and is well known for its involvement in Ewing’s sarcoma and leukemia. “Oncogenic activation of ERG resulting from gene fusion is the most common genetic event in prostate cancer,” said first author Dr. Sheng-You Liao. “ERG plays an important role in prostate tumor initiation and progression. However, the molecular mechanisms driving ERG-mediated tumorigenesis were poorly understood when we began this study. We also hoped to identify genetic vulnerabilities in ERG-positive prostate cancer.”
Since little was known about the functions of ERG in the prostate, they first looked for ERG interacting proteins in normal prostate cells. They found that ERG forms a complex with SND1 (Staphylococcal Nuclease and Tudor Domain containing 1), another poorly characterized protein despite having a well-documented role in cancer. They found that ERG increases the nuclear localization of SND1 and that an SND1 mutant that is constitutively localized to the nucleus is a potent driver of prostate cell proliferation. Conversely, knocking down SND1 in prostate cancer cell lines expressing ERG resulted in decreased proliferation. Analyzing the effect of SND1 and ERG knockdown on gene expression in prostate cells revealed a large overlap. Knocking down both SND1 and ERG did not have an additive effect on gene expression, suggesting that they regulate the same signaling pathways controlling expression of these genes. Finally, they assessed the role of SND1 in a mouse model of ERG-driven prostate cancer by generating the first SND1 inducible knockout mouse. They found that loss of SND1 in the prostate reduced the incidence of prostate tumors in mice and that those tumors that did develop were less aggressive. These findings confirmed that SND1 is a vulnerability for ERG-driven prostate cancer.
Looking to the future, many basic questions remain to be answered about what happens downstream of ERG and SND1 to promote prostate cancer. “We found that ERG increases the nuclear localization of SND1 and nuclear localized SND1 mutant is a much more potent driver of cellular proliferation than the wild-type,” says Dr Liao. “Future experiments will need to address whether ERG is only involved in nuclear retention of SND1, or whether both proteins continue to function together as a complex in mediating growth by SND1 in the nucleus of prostate epithelial cells.” SND1 has multiple nuclease domains and was originally described as a transcriptional co-activator but has since been shown to regulate splicing and miRNA processing as well. Does interaction with ERG affect these SND1 functions? Does the ERG-SND1 interaction cause a gain-of-function? Does SND1 change the function of ERG? “Now that we know these two proteins are important for prostate tumor development, it opens the door to studying these proteins further with the end goal of developing a therapeutic to block the interaction.”
The spotlighted research was funded by the Department of Defense and National Cancer Institute.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Michael Haffner, Pete Nelson, and Valeri Vasioukhin contributed to this work.
Liao SY, Rudoy D, Frank SB, Phan LT, Klezovitch O, Kwan J, Coleman I, Haffner MC, Li D, Nelson PS, Emili A, Vasioukhin V. 2023. SND1 binds to ERG and promotes tumor growth in genetic mouse models of prostate cancer. Nature Communications. 14(1):7435.