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

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.

SUBMITTER: Park CM

PROVIDER: S-EPMC7323895 | biostudies-literature | 2020 Jan-Mar

REPOSITORIES: biostudies-literature

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

Park Chan Mi CM Lee Jae Eun JE Kim Jung Hwa JH

Genetics and molecular biology 20200101 2

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 ...[more]

PMID: 32422649

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Project description:BackgroundRecently, much attention has been focused on gaining a better understanding of the different populations of cells within a tumor and their contribution to cancer progression. One of the most commonly used methods to isolate a more aggressive sub-population of cells utilizes cell sorting based on expression of certain cell adhesion molecules. A recently established method we developed is to isolate these more aggressive cells based on their properties of increased invasive ability. These more invasive cells have been previously characterized as tumor initiating cells (TICs) that have a stem-like genomic signature and express a number of stem cell genes including Oct3/4 and Nanog and are more tumorigenic compared to their 'non-invasive' counterpart. They also have a profile reminiscent of cells undergoing a classic pattern of epithelial to mesenchymal transition or EMT. Using this model of invasion, we sought to investigate which genes are under epigenetic control in this rare population of cells. Epigenetic modifications, specifically DNA methylation, are key events regulating the process of normal human development. To determine the specific methylation pattern in these invasive prostate cells, and if any developmental genes were being differentially regulated, we analyzed differences in global CpG promoter methylation.ResultsDifferentially methylated genes were determined and select genes were chosen for additional analyses. The non-receptor tyrosine kinase BMX and transcription factor SOX1 were found to play a significant role in invasion. Ingenuity pathway analysis revealed the methylated gene list frequently displayed genes from the IL-6/STAT3 pathway. Cells which have decreased levels of the targets BMX and SOX1 also display loss of STAT3 activity. Finally, using Oncomine, it was determined that more aggressive metastatic prostate cancers in humans also have higher levels of both Stat3 and Sox1.ConclusionsUsing this method we can begin to understand which genes are epigenetically regulated in the invasive population compared to the bulk tumor cells. These aggressive sub-populations of cells may be linked to the cancer stem cell hypothesis, making their patterns of epigenetic regulation very attractive for biomarker analysis.

Project description:Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the ninth member of the proprotein convertase family that regulates lipoprotein homeostasis and altered PCSK9 expression was reportedly associated with tumor development and progression. This study assessed PCSK9 expression and functions in human colon cancer and then explored the underlying molecular events. Methods Colon cancer tissues were utilized for analysis of PCSK9 expression for association with clinicopathological factors from patients by immunohistochemistry assay. Manipulation of PCSK9 expression was assessed in vitro and in vivo for colon cancer cell proliferation, migration, and invasion using cell viability CCK-8, Transwell tumor cell migration and invasion, and wound-healing assays. Next, proteomic analysis, Western blot, qRT-PCR and Flow cytometry were conducted to assess downstream targets and tumor cell-derived PCSK9 action on macrophage polarization. Results PCSK9 expression was upregulated in colon cancer tissues versus the normal tissues, and associated with advanced tumor pathological grade. Knockdown of PCSK9 expression reduced colon cancer cell proliferation, migration, and invasion and suppressed tumor metastasis in vivo. PCSK9 directly or indirectly upregulated Snail 1 and in turn to downregulate E-cadherin expression, but upregulate N-cadherin and MMP9 levels and thereafter, to induce colon cancer cell epithelial-mesenchymal transition (EMT) process and activated PI3K/AKT signaling. However, PCSK9 overexpression showed the inverse effects on colon cancer cells. Knockdown of PCSK9 expression inhibited M2 macrophage polarization, but also promoted M1 macrophage polarization by reduction of lactate, protein lactylation and macrophage migration inhibitory factor (MIF) levels. Conclusion PCSK9 played an important role in the progression and metastasis of colon cancer by regulation of tumor cell EMT and PI3K/AKT signaling and in the phenotypic polarization of macrophages by mediating MIF and lactate levels. Targeting PCSK9 expression or activity could be used to effectively control colon cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02477-0.

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

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

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