Targeting BRF2 in Cancer Using Repurposed Drugs

Rashidieh, Behnam; Molakarimi, Maryam; Mohseni, Ammar; Tria, Simon Manuel; Truong, Hein; Srihari, Sriganesh; Adams, Ryan A.; Ma, Jones; Duijf, Pascal H.G.; Kalimutho, Murugan; Khanna, Kum Kum

doi:10.3390/cancers13153778

Cited by 9 publications

(5 citation statements)

References 84 publications

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“…BRF2 upregulation has been observed in many types of cancers and is critical in the development and progression of various cancers, including lung cancer, breast cancer, and esophageal squamous cell cancer [19][20][21][22]41]. However, the functions and clinical relevance of BRF2 in HCC have been largely…”

Section: Discussionmentioning

confidence: 99%

MALAT1/ miR-1-3p-mediated BRF2 promotes HCC progression via inhibiting the LKB1/AMPK signaling pathway

Meng

Pan

et al. 2023

Preprint

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Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and one of the main causes of cancer-related death worldwide. Many studies have shown that abnormal expression of lncRNA plays a crucial role in HCC. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been reported to play a vital role in various tumors. However, the underlying mechanism of MALAT1 in HCC has not been thoroughly elucidated. The expression of MALAT1 were detected by qRT-PCR. Antisense oligonucleotides (ASO)-MALAT1 transfected cells were used to explore the biological effects of MALAT1 by cell CCK-8, colony formation, transwell, wound healing, and flow cytometry analysis. Western blotting was performed to measure PI3K/Akt and apoptosis-related protein levels. Dual-luciferase reporter assay was performed to verify the relationship between MALAT1 and its specific targets. We found that MALAT1 was upregulated, and MALAT1 knockdown inhibited migration and invasion, and it induced apoptosis in vitro and in vivo. Further studies demonstrated that MALAT1 positively regulated the expression of transcription factor II B‑related factor 2 (BRF2) which was associated with clinical index and poor prognosis. Mechanistically, MALAT1 was found to act as a competitive endogenous RNA to sponge hsa-miR-1-3p, which upregulated BRF2. Knockdown of BRF2 inhibited the progression of HCC by the LKB1/AMPK pathway. Overexpression of BRF2 reversed the inhibitory effect of MALAT1 knockdown. Our results demonstrate a novel MALAT1/miR-1-3p/BRF2/LKB1/AMPK regulatory axis in HCC, which may provide new molecular therapeutic targets for HCC in the future.

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Section: Discussionmentioning

confidence: 99%

MALAT1/ miR-1-3p-mediated BRF2 promotes HCC progression via inhibiting the LKB1/AMPK signaling pathway

Meng

Pan

et al. 2023

Preprint

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“…Cell proliferation was performed as previously described [ 9 ]. Cells were plated in a 24-well plate at density of 5000 cells per well in duplicate and cultured overnight.…”

Section: Methodsmentioning

confidence: 99%

Alpha-B-Crystallin overexpression is sufficient to promote tumorigenesis and metastasis in mice

et al. 2023

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Background αB-Crystallin is a heat shock chaperone protein which binds to misfolded proteins to prevent their aggregation. It is overexpressed in a wide-variety of cancers. Previous studies using human cancer cell lines and human xenograft models have suggested potential tumor promoter (oncogene) roles for αB-Crystallin in a wide-spectrum of cancers. Methods To determine the causal relationship between CRYAB overexpression and cancer, we generated a Cryab overexpression knock-in mouse model and monitor them for development of spontaneous and carcinogen (DMBA)-induced tumorigenesis. In order to investigate the mechanism of malignancies observed in this model multiple techniques were used such as immunohistochemical characterizations of tumors, bioinformatics analysis of publically available human tumor datasets, and generation of mouse embryonic fibroblasts (MEFs) for in vitro assays (clonogenic survival and migration assays and proteome analysis by mass-spectrometry). Results This model revealed that constitutive overexpression of Cryab results in the formation of a variety of lethal spontaneous primary and metastatic tumors in mice. In vivo, the overexpression of Cryab correlated with the upregulation of epithelial-to-mesenchymal (EMT) markers, angiogenesis and some oncogenic proteins including Basigin. In vitro, using E1A/Ras transformed MEFs, we observed that the overexpression of Cryab led to the promotion of cell survival via upregulation of Akt signaling and downregulation of pro-apoptotic pathway mediator JNK, with subsequent attenuation of apoptosis as assessed by cleaved caspase-3 and Annexin V staining. Conclusions Overall, through the generation and characterization of Cryab overexpression model, we provide evidence supporting the role of αB-Crystallin as an oncogene, where its upregulation is sufficient to induce tumors, promote cell survival and inhibit apoptosis.

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“…There is another recent study on the transcription factor BRF2, which is among the therapeutic targets as its upregulation is observed in the formation of various types of cancer, but there is no available specific drug targeting BRF2. By performing drug repositioning through virtual screening of drug molecules that are potential candidates for BRF2 inhibition, Rashidieh et al found that the bexarotene molecule led to a serious decrease in the proliferation of this type of cancer cells [97].…”

Section: Virtual Screeningmentioning

confidence: 99%

Fundamentals of Molecular Docking and Comparative Analysis of Protein–Small-Molecule Docking Approaches

Feyza¹,

Selin²,

Acuner-Ozbabacan³

2023

Biomedical Engineering

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Proteins (e.g., enzymes, receptors, hormones, antibodies, transporter proteins, etc.) seldom act alone in the cell, and their functions rely on their interactions with various partners such as small molecules, other proteins, and/or nucleic acids. Molecular docking is a computational method developed to model these interactions at the molecular level by predicting the 3D structures of complexes. Predicting the binding site and pose of a protein with its partner through docking can help us to unveil protein structure-function relationship and aid drug design in numerous ways. In this chapter, we focus on the fundamentals of protein docking by describing docking methods including search algorithm, scoring, and assessment steps as well as illustrating recent successful applications in drug discovery. We especially address protein–small-molecule (drug) docking by comparatively analyzing available tools implementing different approaches such as ab initio, structure-based, ligand-based (pharmacophore-/shape-based), information-driven, and machine learning approaches.

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Targeting BRF2 in Cancer Using Repurposed Drugs

Cited by 9 publications

References 84 publications

MALAT1/ miR-1-3p-mediated BRF2 promotes HCC progression via inhibiting the LKB1/AMPK signaling pathway

MALAT1/ miR-1-3p-mediated BRF2 promotes HCC progression via inhibiting the LKB1/AMPK signaling pathway

Alpha-B-Crystallin overexpression is sufficient to promote tumorigenesis and metastasis in mice

Fundamentals of Molecular Docking and Comparative Analysis of Protein–Small-Molecule Docking Approaches

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