Therapeutic Targeting of Upregulated BAP1 in Human Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC), commonly known as liver cancer, is one of the leading causes of cancer- related death worldwide. Due to its lack of specific symptoms, HCC is frequently diagnosed at the advanced stage, when the treatment options are quite limited. Currently, immunotherapy is the first line treatment option for advanced HCC. However, a significant percentage of patients do not respond. Overall, HCC remains to be a deadly malignancy with poor five-year survival rates. BAP1 has been traditionally viewed as a tumor suppressor. Indeed, heterozygous loss of function germline BAP1 mutations confer an increased risk for a variety of cancers, and this is known as BAP1 Cancer Syndrome. Somatic loss of function mutations of the BAP1 gene could be found in multiple tumor types, including HCC. However, the mutation rate of BAP1 in HCC is very low, representing around 1.9% (23/1209) of all HCC cases analyzed based on the COSMIC database. In contrast, in most human HCCs, BAP1 expression is upregulated and high expression of BAP1 mRNA is associated with poor patient survival. In human HCC cell lines, deletion of BAP1 leads to decreased HCC cell growth. Mechanistically, we discovered that BAP1 may regulate the cholesterol biosynthesis pathway in HCC cells. Based on these preliminary studies, we hypothesize that high BAP1 expression is required for sustained HCC cell growth via regulating cholesterol metabolism, and targeting BAP1 might be effective against this malignancy. To address this hypothesis, we propose two specific aims. In Aim 1, we will investigate the expression and functional roles of BAP1 in promoting HCC progression. In Aim 2, we will determine the therapeutic potential of targeting BAP1 for HCC treatment. In summary, the proposed aims fit well with the R21 funding mechanism as translational exploratory studies. Our innovative approach to investigating the oncogenic roles of BAP1 during HCC pathogenesis is both mechanistic and groundbreaking. The anticipated results hold the potential to pave the way for novel, targeted therapies, offering new hope against this deadly malignancy. Project Number: 1R21CA303374-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Xin Chen | Institution: UNIVERSITY OF HAWAII AT MANOA, HONOLULU, HI | Award Amount: $402,401 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CTH-J (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11350331