The role of PTEN feedback mechanism in cancer

项目总结

Project Summary PTEN (phosphatase and tensin homolog) is among the most commonly altered tumor suppressor genes in human cancers. The overarching premise of this project is twofold. First, while PTEN function can be compromised by genetic mutations in inherited syndromes and sporadic cancers, post-translational modifications (PTMs) of PTEN may play key roles in the dynamic regulation of PTEN function. Prior studies on PTEN PTMs, including our work supported by this award, identified that deregulated ubiquitination and deubiquitination lead to detrimental effects on PTEN stability and subcellular localization, thereby causing tumorigenesis. Secondly, PTEN fulfils many of its tumor suppressive roles through the PI3K-AKT-mTOR pathway; however, the role of PTEN has also been shown to extend beyond the control of PI3K, with PTEN implicated in controlling genomic stability and cell cycle progression, although the mechanism remains unclear. The overall goal of this application is to investigate the mechanisms of nuclear PTEN-mediated tumor suppression, focusing on cancer-specific PTM regulation of PTEN compartmentalization and non-canonical functions independent of its cytoplasmic phosphatase activity. Our new preliminary study revealed the novel upstream PTM mechanism and essential downstream effectors for nuclear PTEN in cancer. Multi-omics analyses of proteome, transcriptome and epigenome revealed a clear link between the PTEN-chromatin remodeling factor axis and genomic integrity within the nucleus. Further, this novel PTEN-associated chromatin remodeling factor conferred synthetic essentiality in cancer cells lacking nuclear PTEN. Based on these observations, we hypothesize that canonical and non-canonical PTEN signaling coordinately reduces tumorigenesis and therapy resistance. To test this hypothesis, we will (1) determine how PTEN PTMs occur and their role in cancer; (2) define the non-canonical roles of PTEN in tumorigenesis and genomic instability; (3) explore the therapeutic potential of the PTEN-chromatin remodeling factor axis in cancer. The completion of this project will not only gain insight into the molecular and cellular mechanisms by which the newly characterized PTM of PTEN tipping the balance between its canonical and non-canonical signaling, but also yield critical information about the development of effective strategies for precision treatment of PTEN loss-of- function driven cancers.