Targeting BAP1 with small compound inhibitor for colon cancer treatment

Our plain-English summary of Targeting BAP1 with small compound inhibitor for colon cancer treatment, by M. Kang, S.G. Park, S.A. Lee, et al (Scientific Reports, 2023).

The study

• Authors: M. Kang, S.G. Park, S.A. Lee, S. Kim, D. Lee, M.E. Shirbhate, S.Y. Youn, K.M. Kim, S.S. Cha, J. Kwon
• Journal: Scientific Reports
• Published: 2023;13(1):2264
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2023. The Author(s).

In plain English

This laboratory study examined the deubiquitinase BAP1 in colon cancer. Using database searches, immunoblotting of eight colon cancer and two normal colon cell lines, and a tissue microarray, the authors found BAP1 was higher in colon cancer: about 77% of colon cancer tissues (83 of 108) but 33% of normal colon tissues (4 of 12) scored BAP1-positive. Depleting BAP1 with siRNA reduced viability in six of eight colon cancer lines (HCT116 and SW48 by more than 80%), increased apoptosis (about 19-, 11- and eightfold in HCT116, SW48 and RKO), slowed replication fork progression and raised the IdU/CldU ratio from about 1 to 1.76 in HCT116, and suppressed tumour growth in nude mice. The compound TG2-179-1 inhibited BAP1 deubiquitinase activity in vitro, killed all eight colon cancer lines (IC50 under 10 micromolar), and slowed xenograft tumour growth (control tumours grew about 23-fold by day 21 versus about 12-fold with TG2-179-1). It also killed normal colon cells and BAP1-deficient mesothelioma and renal carcinoma cells.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: human cell line experiments, biochemical deubiquitinase assays, in silico docking, and mouse xenograft experiments
• Who was studied: Eight colon cancer cell lines and two normal colon cell lines, mesothelioma (MSTO-211H, H226) and clear cell renal carcinoma (786-O, Umrc-6) lines, a tissue microarray of 108 colon cancer and 12 normal colon tissues, and nude mice bearing HCT116 xenografts
• Exposure: Depletion of BAP1 by siRNA, and treatment with the small-compound BAP1 inhibitor TG2-179-1 (cells up to 100 micromolar; mice 10 or 30 mg/kg intraperitoneally three times weekly for three weeks)
• Main results:
  • BAP1 staining was positive in about 77% of colon cancer tissues (83 of 108) versus 33% of normal colon tissues (4 of 12)
  • BAP1 depletion reduced viability in six of eight colon cancer cell lines, with more than 80% reduction in HCT116 and SW48
  • BAP1 depletion increased apoptosis most markedly in HCT116, SW48 and RKO cells (about 19-, 11- and eightfold)
  • In HCT116 cells, the average IdU/CldU ratio rose from about 1 to 1.76 after BAP1 depletion, interpreted by the authors as fork stalling and collapse
  • TG2-179-1 reduced viability of all eight colon cancer cell lines, with IC50 values under 10 micromolar
  • TG2-179-1 was more cytotoxic to BAP1-proficient MSTO-211H mesothelioma cells (IC50 2.39 micromolar) than to BAP1-deficient H226 cells (4.34 micromolar); for renal carcinoma cells, 786-O 6.35 versus Umrc-6 10.4 micromolar
  • In HCT116 xenografts, tumour volume in control mice increased about 23-fold by day 21 versus about 12-fold in TG2-179-1-treated mice, with no significant difference between the 10 and 30 mg/kg doses
  • TG2-179-1 also killed CCD-18Co and CCD-112CoN normal colon cells, which the authors state express BAP1 at very low levels
• The authors' conclusion: The authors concluded that BAP1 acts oncogenically in colon cancer and is a potential therapeutic target, and that TG2-179-1 could be developed as a potential therapeutic agent for colon cancer
• Limitations the authors state:
  • The authors state TG2-179-1 also acts through BAP1-independent mechanisms and is not cancer cell specific, likely having off-targets
  • The authors could not confirm covalent binding at Cys91 by mass spectrometry
  • The authors state the compound appears not to be stable enough to retain cytotoxic activity for an extended period

Topics

The National Library of Medicine indexes this study under subjects our site covers: Colon cancer.

Medical terms in this study, explained in our Lexicon: BAP1, Colorectal Cancer, Mesothelioma, Carcinoma, Apoptosis.

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• Usp9x- and Noxa-mediated Mcl-1 downregulation contributes to pemetrexed-induced apoptosis in human non-small-cell lung cancer cells — J. Yan, N. Zhong, et al. (2014)
• Positive nuclear BAP1 immunostaining helps differentiate non-small cell lung carcinomas from malignant mesothelioma — M. Carbone, D. Shimizu, et al. (2016)
• Loss of expression of BAP1 is very rare in non-small cell lung carcinoma — J. Andrici, T.R. Parkhill, et al. (2016)
• Loss of BRCA1-associated protein 1 (BAP1) expression is rare in non-small cell lung cancer — D. Owen, B.S. Sheffield, et al. (2017)

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