- Research findings published in the globally renowned journal Cancer Communications (Impact Factor: 24.9)

- Reveals the molecular mechanism underlying DKK1-mediated liver cancer proliferation and metastasis

- Proposes a novel anticancer strategy utilizing the “PPO domain” to minimize side effects on normal cells

  The research team led by Professor Eek-hoon Jho of the Department of Life Science, College of Natural Sciences at the University of Seoul, in collaboration with the research team led by Professor Cheong Jaeyoun of Ajou University, announced that they have identified a novel cancer-specific therapeutic strategy capable of suppressing the proliferation and metastasis of liver cancer.

  The findings were published in Cancer Communications (Impact Factor: 24.9; top 3.5% in Journal Citation Reports [JCR]), a globally renowned journal in cancer research, under the title “DKK1 Suppresses Hippo Signaling via PIP₃–OGT–LRP6 O-GlcNAcylation in Hepatocellular Carcinoma.”

  The research team identified the detailed molecular mechanism through which “DKK1,” a secreted protein overexpressed in liver cancer, promotes abnormal proliferation and metastasis of cancer cells. While previous studies focused primarily on PIP₃ formation induced by DKK1, this study is the first to demonstrate that “O-GlcNAcylation,” a unique post-translational modification of the receptor protein “LRP6,” serves as a key molecular mechanism underlying DKK1-mediated cancer cell growth.

  The study further confirmed that DKK1-induced O-GlcNAcylation of LRP6 suppresses “Hippo signaling,” a tumor-suppressive signaling pathway in liver cancer tissue, thereby activating the oncogenic protein “YAP” and dramatically increasing the proliferation and metastatic capacity of cancer cells.

  To block this carcinogenic process, the research team proposed an innovative “PIP₃ masking” strategy utilizing the “PPO (PIP3-binding domain of OGT)” domain.

  Conventional O-GlcNAcylation inhibitors have raised concerns regarding adverse side effects because they inhibit not only cancer cells but also the metabolism of normal cells. However, the PPO strategy developed by the research team acts selectively within localized regions of the cell membrane. Using this approach, the team successfully inhibited the O-GlcNAcylation modification of LRP6 located on the cell membrane, thereby reactivating Hippo signaling and effectively suppressing the YAP protein.

  In particular, this strategy demonstrated broad anticancer effects not only in liver cancer characterized by high DKK1 expression but also in conditions involving elevated PIP₃ levels commonly observed across various cancer types. In contrast, minimal effects were observed in normal cells with low DKK1 expression or minimal PIP₃ formation, highlighting the potential of this approach as a cancer-specific precision therapy.

  Professor Eek-hoon Jho of the University of Seoul stated, “This study is highly meaningful in that it presents a new therapeutic strategy that could offer hope to patients with advanced liver cancer for whom effective treatments are limited.” He added, “Because the PPO strategy has broad applicability across various cancer types, it could be further developed into a patient-tailored precision anticancer therapy platform based on DKK1 expression levels.”

▶ (From left) Doctoral candidate Ukjin Lee, doctoral candidate Hyewon Shim, and Professor Eek-hoon Jho

  This research was conducted with support from the National Research Foundation of Korea (NRF), the BK21 Program, and other funding initiatives.

  This achievement is regarded as a study that proposes a novel anticancer strategy grounded in a robust molecular mechanism. By minimizing side effects on normal cells while maximizing therapeutic efficacy, the study establishes an important foundation for patient-tailored precision medicine and the development of broadly applicable anticancer therapeutics.