Exploiting genetic vulnerabilities for BAP1 loss by synthetic lethality

 BAP1 is a powerful tumor suppressor gene that is frequently mutated in different tumor types, such as renal cell carcinoma, uveal melanoma and cholangiocarcinoma. We previously found that BAP1 loss is associated with aggressive tumors, metastasis and poor patient survival. Unfortunately, there are no specific treatments for tumors with mutations in BAP1. Thus, the aim of this project is the identification of synthetic lethal targets of BAP1‑mutated tumor entities using a large‑scale RNA interference screen. We found HDAC1 as one of the most prominent hits. After knockdown of HDAC1, a decrease of proliferation and colony formation in BAP1-deficient cell lines but not in BAP1-expressed cell lines could be analyzed. Besides, by treating cells with the HDAC1 inhibitor Quisinostat,we detected a stronger decrease of the cell viability of BAP1‑deficient cell lines compared to BAP1 wild-type cell lines. Additionally, HDAC1 knockdown had a higher efficiency suppressing the migration of BAP1-null cells compared to BAP1-competent cells. Characterizing the role of HDAC1, a G1 arrest in BAP1-deficient cell lines could be uncovered, which was not associated with an increase of apoptosis. Furthermore, in vivo studies in mice revealed a significant decrease of tumor formation after HDAC1 knockdown in BAP1-deficient tumors, strongly suggesting HDAC1 as a true synthetic lethal interactor with BAP1 loss. Based on our data, HDAC1 inhibitors might be effective for treating patients with mutations in BAP1.


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