BAP1 functions as a tumor promoter in prostate cancer cells through EMT regulation

Our plain-English summary of BAP1 functions as a tumor promoter in prostate cancer cells through EMT regulation, by C.M. Park, J.E. Lee, J.H. Kim (Genetics and Molecular Biology, 2020).

The study

• Authors: C.M. Park, J.E. Lee, J.H. Kim
• Journal: Genetics and Molecular Biology
• Published: 2020;43(2):e20190328
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

BRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme that has long been considered to be a tumor suppressor in various tumors, including renal cell carcinoma, uveal melanoma, mesothelioma, and cutaneous melanoma. However, the involvement of BAP1 in the progression of prostate cancer has not been studied until recently. Herein, we investigated the tumor promoting function of BAP1 in the context of prostate cancer. Analysis of The Cancer Genome Atlas (TCGA) data set showed that prostate cancer patients express high levels of BAP1 mRNA. High BAP1 expression is inversely correlated with disease-free survival in patients with prostate cancer. Among the prostate cell lines tested, BAP1 expression was high in tumorigenic and metastatic cell lines, but was low in normal prostate cell line. Knockdown of BAP1 in PC3 or DU145 cells induced mesenchymal-to-epithelial transition (MET). Further, BAP1-knockdown resulted in decreased migration and invasion of PC3 and DU145 cells. Conversely, overexpression of BAP1 in RWPE1, a normal prostate cell line, induced the migratory and invasive properties. Collectively, our findings identified that BAP1 has a tumor promoting function in prostate cancer cells, and suggest that BAP1 can serve as a potential therapeutic target for prostate cancer.

In plain English

This laboratory study examined BAP1, a deubiquitinating enzyme usually described as a tumor suppressor in cancers such as mesothelioma, uveal melanoma and renal cell carcinoma, in the setting of prostate cancer; it did not study asbestos or mesothelioma patients. The authors analyzed public gene-expression data and ran cell-culture experiments. In the TCGA prostate dataset, BAP1 mRNA was higher in cancer samples (n = 497) than normal samples (n = 52) (p < 0.0001, Wilcoxon rank sum test). In a separate dataset (GEO GSE21302) analyzed through cBioPortal, BAP1 was higher in 19 metastatic than 131 primary tumors (p < 0.01). In TCGA, patients with high BAP1 expression had worse disease-free survival than those with low expression (p < 0.01, log-rank). BAP1 protein was high in RWPE2, LNCaP, PC3 and DU145 cells and low in the normal prostate line RWPE1. Knocking BAP1 down in PC3 and DU145 reduced proliferation, migration and invasion and induced mesenchymal-to-epithelial transition, with increased E-cadherin and decreased vimentin, Twist, Snail, MMP2, MMP7, MMP9 and VEGFA. Overexpressing BAP1 in RWPE1 increased migration and invasion; the hydrolase-deficient C91S mutant did not.

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 combining analysis of public tumor gene-expression and survival databases with human prostate cell line experiments (shRNA knockdown and overexpression)
• Who was studied: Public data: TCGA-PRAD normal (n = 52), cancer (n = 497) and metastasis (n = 1) samples; a separate dataset accessed via cBioPortal (GEO GSE21302) with 131 primary and 19 metastatic prostate tumors; TCGA-PRAD disease-free survival data for 491 patients (reported as 492 in the Results); and prostate cell lines RWPE1, RWPE2, LNCaP, PC3, DU145
• Exposure: Manipulation of BAP1 levels: stable shRNA knockdown of BAP1 in PC3 and DU145 cells, and overexpression of wild-type BAP1 or the ubiquitin hydrolase activity-deficient mutant BAP1 C91S in RWPE1 cells (no asbestos or fiber exposure studied)
• Main results:
  • In the TCGA dataset, BAP1 mRNA was higher in prostate carcinoma tissue (n = 497) than in normal tissue (n = 52)
  • In the cBioPortal data from GEO GSE21302, BAP1 mRNA was higher in metastatic (n = 19) than primary (n = 131) prostate cancer samples
  • Patients with high BAP1 expression had worse disease-free survival than those with low expression
  • BAP1 protein was high in tumorigenic and metastatic prostate cell lines and low in the normal line RWPE1
  • BAP1 knockdown in PC3 and DU145 slowed proliferation
  • BAP1 knockdown produced mesenchymal-to-epithelial transition markers in PC3 and DU145 cells
  • BAP1 knockdown lowered the EMT-inducing transcription factors Twist and Snail in both cancer lines
  • BAP1 knockdown lowered expression of three matrix metalloproteases
  • VEGFA expression also fell after BAP1 knockdown
  • BAP1 knockdown reduced wound healing in the tested prostate cancer cells
  • BAP1 knockdown reduced transwell migration of prostate cancer cells
  • BAP1 knockdown reduced invasion through Matrigel
  • In normal RWPE1 cells, wild-type BAP1 overexpression increased proliferation while the C91S mutant did not
  • Wild-type BAP1 overexpression increased migration and invasion of RWPE1 cells, but the hydrolase-deficient C91S mutant did not
• The authors' conclusion: The authors concluded that BAP1 acts as a tumor promoter in prostate cancer cells, dependent on its ubiquitin hydrolase activity, and suggested it as a possible therapeutic target
• Limitations the authors state:
  • The authors stated that BAP1's roles in cancer progression are diverse and context-dependent and that a specific BAP1 substrate in prostate cancer still needs to be identified
  • The proposed mechanism through deubiquitination of H2AK119ub was presented as a possibility, not a demonstrated finding

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Carcinoma, Mesothelioma, Disease-Free Survival.

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