Cracking the rRNA modification code in cancer

About This Grant

PROJECT ABSTRACT / SUMMARY The ribosome is a fine-tuned regulator of gene expression through multiple layers of regulation, including post- transcriptional RNA modifications. Cancer cells have “hijacked” the translation machinery to exert rapid and selective translational control of the cancer proteome in a matter that is distinct from normal cells. Changing the landscape of the hundreds of modifications in the catalytic core of the ribosome may be one of the strategies cancer cells use to reprogram their translatome. Work from our labs has been the first to demonstrate a functional link between rRNA modifications and cancer etiology. We have discovered that one of the most deregulated oncogenic signals, RAS, directly controls the expression of multiple snoRNAs, which are small non-coding RNAs that guide rRNA modifications. As a paradigm example, we have shown that one of the snoRNAs, SNORA24, plays a pivotal role in bypassing oncogene-induced senescence (OIS), a critical tumor-suppressive mechanism. We attribute this profound effect of a snoRNA on cancer progression due to its role in controlling lipid metabolism, a key feature of cancer development. This is reinforced by our findings that SNORA24 controls the translation of lipid metabolism transcripts, which is recognized as one of the hallmarks of liver cancer. We further show that additional snoRNAs driven by RAS expression are critical for cell fitness of colon cancer cells and have opposing roles on control of global protein synthesis. In cancer, the dysregulation of these modifications has been increasingly recognized as a contributor to tumor development, progression, and drug resistance. However, a systematic analysis of snoRNA function in cancer biology, the mechanistic and biochemical basis for their function as well as the breadth of these modifications for distinct human cancers is lacking. Here we will combine the expertise of our two labs as well as collaborators to (1) mechanistically dissect the biochemical and structural basis for rRNA modifications on control of cancer metabolism, (2) use state-of-the-art CRISPR screen to directly assess snoRNA function in different steps of tumorigenesis in-vivo and whether this is guided directly by rRNA modifications, as well as (3) create an atlas of all RNA modification changes in primary human prostate cancer and their impact on the cancer translatome. In addition, here we will build off of a novel technology known as Pan-Mod-Seq that can simultaneously measure all known rRNA modifications in dozens of cancer samples at the same time. We will be in a strong position to further analyze the prospective and retrospective associations of these modifications on cancer progression, metastasis and therapeutic response. Understanding the role of rRNA modifications in cancer will provide insights into disease mechanisms and open new avenues for diagnostic biomarkers and therapeutic interventions.