Deciphering the regulatory mechanism… (F31CA306106) – Project Grant to The Regents Of The University Of…

Abstract: /project summary this project aims to elucidate how the EYA3/PP2A-B55Α complex regulates NF-KB signaling in addition to MYC stability, two critical oncogenic pathways, and how to inhibit EYA3 and PP2A-B55Α interaction to target both pathways. MYC and NF-ΚB are key regulators of cell proliferation, metabolism, immune modulation, and inflammation, and both play major roles in driving cancer progression, particularly in aggressive subtypes like triple-negative breast cancer (tnbc). Our published data suggest that EYA3, by recruiting PP2A-B55Α, promotes MYC stability through dephosphorylation at THR58 and our preliminary data shows that EYA3 and PP2A-B55Α facilitates NF-ΚB activation via a mechanism that remains largely unexplored. The long-term goal of this research is to establish EYA3/PP2A-B55Α as a multi-functional target that disrupts both MYC and NF-ΚB signaling, offering a novel strategy to suppress tumor growth and immune suppression in cancer. The project has two main objectives: (1) to identify the molecular interactions through which EYA3/PP2A-B55Α modulates NF-ΚB signaling, including characterizing the phosphatase targets and interactions within the IKK complex; and (2) to develop and evaluate a cell-penetrating peptide (CPP) inhibitor to block the EYA3-PP2A interaction, providing both a potential therapeutic tool and a valuable research probe for understanding EYA3-mediated signaling. This fellowship will provide comprehensive training in structural biology, molecular oncology, and therapeutic development under the mentorship of experts in breast cancer metastasis and structural biology, DRS. RUI zhao and heide ford. The research environment at the university of colorado cancer center offers access to state-of-the-art facilities and a collaborative atmosphere for translational cancer research, making IT an ideal setting for training in advanced experimental methodologies and for understanding signaling pathways relevant to cancer and public health. By integrating structural biology with cancer signaling research, this project aims to fill key gaps in our knowledge of MYC and NF-ΚB regulation, and establish EYA3/PP2A-B55Α as a critical node in these processes. The insights gained will help reveal how immune modulation, tumor progression, and metastasis can be influenced by EYA3. The findings are expected to lay the foundation for novel therapeutic strategies that target these pathways simultaneously, ultimately improving treatment outcomes, enhancing immune responses, and providing new hope for patients with aggressive cancers.

Deciphering the regulatory mechanism and therapeutic targeting of EYA3/PP2A-B55A in NF-KB signaling

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