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Family history and genetic testing. a Patient's pedigree. The patient's two sisters and her mother do not carry the BAP1 PV. Her father has not been tested. There are no known cases of malignant mesothelioma, uveal or cutaneous melanoma or renal cell carcinoma
Source publication
BAP1 cancer syndrome is a rare and highly penetrant hereditary cancer predisposition. Uveal melanoma, mesothelioma, renal cell carcinoma (RCC) and cutaneous melanoma are considered BAP1 cancer syndrome core cancers, whereas association with breast cancer has previously been suggested but not confirmed so far. In view of BAP1 immunomodulatory functi...
Context in source publication
Context 1
... nab-paclitaxel, which was later discontinued). b After 5 months of treatment, a complete response in the superior mediastinum was seen on CT. d, f After 8 months, there was also a complete response in the supraclavicular region for genetic testing. He subsequently developed a locally advanced prostate cancer. Our patient's pedigree is shown in Fig. ...
Citations
... By 2022, some 234 families and 175 pathogenic or likely pathogenic germline BAP1 variants have been reported and the inclusion of other less frequent tumors in the BAP1-TPDS tumor phenotype is being discussed. Among these are squamous and basal cell carcinoma (7%), meningioma (2%), breast cancer, hepatic and cholangiocarcinoma, and ovarian cancer [1,[4][5][6][7]. Additionally, pathogenic de novo missense variants causing loss of function have been identified in association with the newly found and phenotypically variable syndromic neurodevelopmental disorder known as Kury-Isidor syndrome (OMIM 619762), with undetermined risk of cancer [8]. ...
Background
Pathogenic germline variants in BRCA1-Associated Protein 1 (BAP1) cause BAP1 tumor predisposition syndrome (BAP1-TPDS). Carriers run especially a risk of uveal (UM) and cutaneous melanoma, malignant mesothelioma, and clear cell renal carcinoma. Approximately half of increasingly reported BAP1 variants lack accurate classification. Correct interpretation of pathogenicity can improve prognosis of the patients through tumor screening with better understanding of BAP1-TPDS.
Methods
We edited five rare BAP1 variants with differing functional characteristics identified from patients with UM in HAP1 cells using CRISPR-Cas9 and assayed their effect on cell adhesion/spreading (at 4 h) and proliferation (at 48 h), measured as cell index (CI), using xCELLigence real-time analysis system.
Results
In BAP1 knockout HAP1 cultures, cell number was half of wild type (WT) cultures at 48 h (p = 0.00021), reaching confluence later, and CI was 78% reduced (p < 0.0001). BAP1-TPDS-associated null variants c.67+1G>T and c.1780_1781insT, and a likely pathogenic missense variant c.281A>G reduced adhesion (all p ≤ 0.015) and proliferation by 74%–83% (all p ≤ 0.032). Another likely pathogenic missense variant c.680G>A reduced both by at least 50% (all p ≤ 0.032), whereas cells edited with likely benign one c.1526C>T grew similarly to WT.
Conclusions
BAP1 is essential for optimal fitness of HAP1 cells. Pathogenic and likely pathogenic BAP1 variants reduced cell fitness, reflected in adhesion/spreading and proliferation properties. Further, moderate effects were quantifiable. Variant modelling in HAP1 with CRISPR-Cas9 enabled functional analysis of coding and non-coding region variants in an endogenous expression system.
Med1 binds to a nuclear receptor and regulates transcription. Elevated Med1 protein expression promotes cancer growth in hormone-dependent breast and prostate cancers. Med1 protein expression was investigated by deubiquitinating enzymes (DUBs) overexpression in breast cancer cell lines. Various DNA constructs of SRT-DUBs were overexpressed in the MCF7 cell line, and Med1 protein expression was investigated by western blotting. The cell growth and in vitro invasion assay were performed in BRCA1-associated protein 1 (BAP1) wild type and mutant (C91A) overexpressed cells. Ubiquitination of the Med1 protein was observed, and Med1 protein expression and transcriptional activity were verified by various DUBs overexpressed. Although Med1 protein expression increased upon the overexpression of BAP1, it was not affected by the overexpression of BAP1 mutant (C91A). BAP1 was increased by the E2 treatment, which has an important effect on the breast cancer growth, and cell growth was decreased by BAP1 C91A overexpression. However, metastatic capacities were decreased by BAP1. In addition, the binding between the Med1 and the BAP1 protein was observed. These data suggested that BAP1 regulated Med1 protein expression in breast cancer cells and involved in cancer cell growth and metastasis by binding to Med1 protein.
Med1, a subunit of the TRAP/mediator complex acts as a transcriptional regulatory mediator, binds to a nuclear receptor and regulated transcription. It is known that elevated Med1 protein expression promotes cancer growth in hormone-dependent breast and prostate cancer, whereas low expression of Med1 protein in melanoma and lung cancer increases cancer metastasis. In this study, Med1 protein expression by deubiquitinating enzymes (DUBs) overexpression was investigated in breast and lung cancer cell lines. Overexpression of BAP1 protein did not affect Med1 mRNA expression in breast cancer and lung cancer cell. However, Med1 protein expression decreased in breast cancer cells while increased in lung cancer cell lines. In addition, Med1 protein expression by overexpression of BAP1 mutant (C91A) in breast and lung cancer cells was not affected. Increased BAP1 expression increased cell growth and metastatic capacity in lung cancer cells. And overexpression of BAP1 in breast cancer cell lines increased the transcriptional regulation of estrogen receptor (ER). In addition, the binding between the Med1 and the BAP1 protein was observed. Therefore, these data suggested that BAP1 was involved in cancer cell growth and metastasis by binding to Med1 protein and regulating Med1 protein expression depending on the cancer cell types.
Regarding the multimechanistic nature of cancers, current chemo- or radiotherapies often fail to eradicate disease pathology, and frequent relapses or resistance to therapies occur. Brain malignancies, particularly glioblastomas, are difficult-to-treat cancers due to their highly malignant and multidimensional biology. Unfortunately, patients suffering from malignant tumors often experience poor prognoses and short survival periods. Thus far, significant efforts have been conducted to discover novel and more effective modalities. To that end, modulation of the ubiquitin-proteasome system (UPS) has attracted tremendous interest since it affects the homeostasis of proteins critically engaged in various cell functions, for example, cell metabolism, survival, proliferation, and differentiation. With their safe and multimodal actions, phytochemicals are among the promising therapeutic tools capable of turning the operation of various UPS elements. The present review, along with an updated outline of the role of UPS dysregulation in multiple cancers, provided a detailed discussion on the impact of phytochemicals on the UPS function in malignancies, especially brain tumors.
