Project 1: Unveiling the cell-autonomous and -nonautonomous functions of ITCH in cancer cells and the tumor-immune interface
ITCH is a ubiquitin E3 ligase named after the “itchy” phenotype from the Itch-/- mice. We recently reported an oncogenic function of ITCH through promoting BRAF activation in BRAF wild-type melanoma cells (Yin Q, et al., Nature Communications 2019). This finding elucidated the mechanism by which BRAF wild-type melanoma cells hijack the pro-inflammatory signals to activate the BRAF oncogenic pathway. In addition to its cell autonomous functions, ITCH has been well characterized as a key molecule in regulating adaptive immunity, particularly in several types of T help cells. The roles of ITCH in tumorigenesis are rather controversial due to its versatile functions in both tumor and immune cells. Therefore, an in-depth characterization of ITCH in tumorigenesis considering both tumor and immune cells is warranted to fill the gap in our current knowledge of ITCH’s function in cancer. This research program will provide important mechanistic insights into the context-dependent functions of ITCH in tumor cells and their surrounding microenvironment. There are currently no effective and specific ITCH inhibitors available, therefore, our research will eventually pave the way to the development of ITCH inhibitors in the near future.
Project 2: The Anaphase-Promoting Complex in human cancers
The Anaphase-Promoting Complex (APC) is a multi-subunit ubiquitin E3 ligase complex that functions as the master regulator in cell cycle progression. Although the role of APC in the cell cycle has been well-documented, its functions in human cancers remain largely elusive. Our research is focused on the two substrate-recruiting subunits of APC, namely FZR1 and Cdc20. We have reported that melanocyte-specific deletion of Fzr1 and Pten led to hyperplasia in the mice (Wan L, et al., Cancer Discovery 2017), and that heterozygosity of both Fzr1 and Pten is sufficient to trigger breast tumor onset in the mice (Han T, et al., Nature Communications 2019). These findings suggest that FZR1 has tumor suppressor roles in melanoma and breast cancer. Intriguingly, FZR1 is not frequently deleted or mutated in most human cancers, indicating other mechanisms that repress FZR1. Therefore, understanding how FZR1 is silenced in tumor cells will help us to target this important cell cycle regulator in human cancers. In contrast to FZR1, Cdc20 is overexpressed in the majority of human cancers, and depleting Cdc20 restrains cancer cell proliferation in vitro and in vivo. Mechanistically, we have shown that Cdc20 targets the pro-apoptotic protein Bim for proteolysis in mitosis, such that Cdc20 overexpression in human cancers renders tumor cells resistant to antimitotic agent therapy (Wan L, et al., Developmental Cell 2014). Looking forward, an in-depth characterization of tumor suppressor roles of FZR1 and oncogenic functions of Cdc20 using genetically engineered mouse models and multi-omics profiling will expose therapeutic vulnerabilities in FZR1-deficient and Cdc20-amplified cancers. We are particularly interested in developing approaches to restore FZR1 tumor suppressor function and to destabilize Cdc20 using molecular glues.
Project 3: Identifying PRC2-dependent and PRC2-independent therapeutic vulnerability of EZH2 in human cancers
The Polycomb Repressive Complex 2 mainly functions as the methyltransferase to place H3K27me3 on the chromatin, which suppresses gene expression. EZH2 is the predominant catalytic subunit for this complex in most solid tumor cells. Although small molecule EZH2 inhibitor tazemetostat has been approved by FDA for treatment of follicular lymphoma, EZH2 inhibitors often display limited efficacy in solid tumors. We have identified AMPK as an upstream kinase of EZH2 (Wan et al. Molecular Cell 2018). Consistent with clinical observations, we found that although depleting EZH2 in ovarian cancer cells significantly slows ovarian cancer cell proliferation, EZH2 inhibitors, however, exhibit marginal effectiveness in inhibiting ovarian cancer growth. These results suggest a yet uncharacterized PRC2-independent function of EZH2 in ovarian cancer. In this project, we aim to investigate how AMPK-mediated EZH2 phosphorylation at T311 reshapes EZH2’s interactome, and more importantly, to define the transcriptome governed by this signaling module in ovarian cancer. The long-term goals of this project are to characterize a PRC2-independent role of EZH2 in ovarian cancer, to provide the rationale for the combination of EZH2 degrader and AMPK agonist in future ovarian cancer treatment.