Targeting BAP1 with small compound inhibitor for colon cancer treatment

Abstract

BRCA1-associated protein-1 (BAP1) is a ubiquitin C-terminal hydrolase domain-containing deubiquitinase. The gene encoding BAP1 is mutated in various human cancers, including mesothelioma, uveal melanoma and renal cell carcinoma. BAP1 plays roles in many cancer-related cellular functions, including cell proliferation, cell death, and nuclear processes crucial for genome stability, such as DNA repair and replication. While these findings suggest that BAP1 functions as a tumor suppressor, recent data also suggest that BAP1 might play tumor-promoting roles in certain cancers, such as breast cancer and hematopoietic malignancies. Here, we show that BAP1 is upregulated in colon cancer cells and tissues and that BAP1 depletion reduces colon cancer cell proliferation and tumor growth. BAP1 contributes to colon cancer cell proliferation by accelerating DNA replication and suppressing replication stress and concomitant apoptosis. A recently identified BAP1 inhibitor, TG2-179-1, which seems to covalently bind to the active site of BAP1, exhibits potent cytotoxic activity against colon cancer cells, with half-maximal inhibitory concentrations of less than 10 μM, and inhibits colon tumor growth. TG2-179-1 exerts cytotoxic activity by targeting BAP1, leading to defective replication and increased apoptosis. This work therefore shows that BAP1 acts oncogenically in colon cancer and is a potential therapeutic target for this cancer. Our work also suggests that TG2-179-1 can be developed as a potential therapeutic agent for colon cancer.

High BAP1 expression is associated with poor prognosis in patients with colorectal liver metastases

“…Previous studies have provided con icting evidence, and the role of BAP1 seems to be context-dependent. Regarding the role of BAP1 in CRC, only two studies have explored the association between BAP1 expression and prognosis, demonstrating con icting results [17,18] . One study demonstrated that low BAP1 expression was an independent factor for poor prognosis in patients with CRC [18] .…”

“…One study demonstrated that low BAP1 expression was an independent factor for poor prognosis in patients with CRC [18] . However, another study demonstrated that elevated BAP1 expression was observed in colon cancer and was signi cantly associated with poor prognosis, probably through the regulation of cell proliferation, apoptosis, and DNA replication [17] . In the present study, BAP1 expression was rarely observed in normal gland cells of the colon.…”

“…Therefore, the functional role of BAP1 in tumor biology is controversial and may depend on cancer and cell types. Regarding the role of BAP1 in CRC, two studies have demonstrated con icting evidence regarding whether BAP1 is a tumor suppressor or promoter [17,18] .…”