PhD Candidate: Yijun Gu
Small cell lung cancer (SCLC) is a deadly neuroendocrine malignancy with rapid proliferation, early metastasis, limited immune recognition, and few effective therapies. Despite the near-universal loss of tumor suppressor RB1, its downstream vulnerabilities remain underexploited. To address this, we identified UHRF1, an epigenetic integrator and chromatin modifier, as a critical effector of RB1 loss and a therapeutic liability in SCLC.
My work established UHRF1 as a driver of immune evasion, metastasis, and neuroendocrine phenotype maintenance across major SCLC subtypes. Mechanistically, UHRF1 enhances metastasis through the GATA2–ST6GALNAC5 axis, and interacts with DNMT1 to promote aberrant methylation and repression of tumor suppressors. Its loss impairs tumor growth and metastasis, increases immune infiltration, and elevates expression of cancer-testis antigens.
Given the absence of direct UHRF1 inhibitors, I explored the therapeutic potential of targeting USP7, a deubiquitinase that stabilizes UHRF1 protein. Using both genetic depletion and selective inhibitors (FT671, XL177A), I demonstrated that USP7 suppression triggers proteasomal degradation of UHRF1, mimicking UHRF1 knockout and inhibiting tumor progression in orthotopic SCLC models. While USP7 inhibition largely phenocopies UHRF1 loss, proteomic profiling suggests USP7 also regulates other oncogenic pathways independently of UHRF1, underscoring both the promise and complexity of USP7-targeted therapies.
Collectively, this dissertation establishes UHRF1 as a critical oncogenic driver and therapeutic vulnerability in SCLC and proposes USP7 inhibition as a viable strategy to suppress UHRF1 activity in the absence of direct inhibitors. These findings contribute to a deeper understanding of RB1-loss–driven oncogenesis in SCLC and offer a broader framework for targeting UHRF1 in RB1-deficient cancers.
