BRD4 drives esophageal squamous cell carcinoma growth by promoting RCC2 expression

Wu, Qiong; Liu, Fangfang; Ge, Ming; Laster, Kyle Vaughn; Wei, Lixiao; Du, Ruijuan; Jiang, Ming; Zhang, Jing; Zhi, Yong; Jin, Guoguo; Zhao, Simin; Kim, Dong Joon; Dong, Zigang; Liu, Kangdong

doi:10.1038/s41388-021-02099-4

Cited by 22 publications

(11 citation statements)

References 63 publications

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“…Previous studies have suggested that knockdown of METTL14, FTO, ALKBH5, or YTHDF2 has a stronger inhibitory effect on leukemogenesis than on normal hematopoiesis and that m6A RNA methylation is important in the occurrence and progression of AML, suggesting that m6A regulators may serve as potential therapeutic targets for the eradication of leukemia cells. Through a literature review, we found that RCC2 has been reported to be an oncogene and that overexpression of RCC2 induced epithelial-mesenchymal transition to promote the proliferation, invasion, and migration of lung adenocarcinoma cells; RCC2 can also be driven by BRD4 to promote the growth of esophageal squamous cell carcinoma, although this has not been reported in leukemia 35 – 38 . Recently, FB23 and FB23-2, novel small molecule FTO inhibitors, were identified to selectively inhibit m6A demethylase activity and significantly inhibit the development of human AML cell lines and primary cells in xenograft mice 14 .…”

Section: Discussionmentioning

confidence: 99%

The m6A reader IGF2BP3 promotes acute myeloid leukemia progression by enhancing RCC2 stability

Zhang

Shen

et al. 2022

Exp Mol Med

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N6-methyladenosine (m6A) is the most abundant posttranscriptional modification of mRNA in eukaryotes. Recent evidence suggests that dysregulated m6A-associated proteins and m6A modifications play a pivotal role in the initiation and progression of diseases such as cancer. Here, we identified that IGF2BP3 is specifically overexpressed in acute myeloid leukemia (AML), a subtype of leukemia associated with poor prognosis and high genetic risk. IGF2BP3 is required for maintaining AML cell survival in an m6A-dependent manner, and knockdown of IGF2BP3 dramatically suppresses the apoptosis, reduces the proliferation, and impairs the leukemic capacity of AML cells in vitro and in vivo. Mechanistically, IGF2BP3 interacts with RCC2 mRNA and stabilizes the expression of m6A-modified RNA. Thus, we provided compelling evidence demonstrating that the m6A reader IGF2BP3 contributes to tumorigenesis and poor prognosis in AML and can serve as a target for the development of cancer therapeutics.

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Section: Discussionmentioning

confidence: 99%

The m6A reader IGF2BP3 promotes acute myeloid leukemia progression by enhancing RCC2 stability

Zhang

Shen

et al. 2022

Exp Mol Med

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“…4 , 6 BRD4 has been reported as an important transcriptional activator in tumorigenesis and usually regulates transcriptional activation of oncogenes by binding to acetylated lysines and recruiting specific transcription factors (such as CDK9). 27 , 56 , 57 , 58 , 59 Previous studies have suggested that BRD4 was closely implicated in regulating PI3K/Akt signaling activation in oncogenesis, but the specific mechanisms remain unclear. 60 , 61 Our study for the first time revealed that DDX55 might interact with BRD4 to form a transcriptional regulatory complex, which was responsible for the transcriptional activation of PIK3CA as well as corresponding phenotypic changes of HCC cells.…”

Section: Discussionmentioning

confidence: 99%

“…Emerging evidence has suggested that DEAD‐box proteins generally function as components of multi‐protein complexes and act as a transcriptional co‐activator in gene expression regulation 4,6 . BRD4 has been reported as an important transcriptional activator in tumorigenesis and usually regulates transcriptional activation of oncogenes by binding to acetylated lysines and recruiting specific transcription factors (such as CDK9) 27,56–59 . Previous studies have suggested that BRD4 was closely implicated in regulating PI3K/Akt signaling activation in oncogenesis, but the specific mechanisms remain unclear 60,61 .…”

Section: Discussionmentioning

confidence: 99%

DDX55 promotes hepatocellular carcinoma progression by interacting with BRD4 and participating in exosome‐mediated cell‐cell communication

Zhou

Long

et al. 2022

Cancer Science

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The involvement of DEAD‐box helicase 55 (DDX55) in oncogenesis has been suggested, but its biological role in hepatocellular carcinoma (HCC) remains unknown. The present study verified the upregulation of DDX55 in HCC tissues compared with non‐tumor controls. DDX55 displayed the highest prognostic values among the DEAD‐box protein family for recurrence‐free survival and overall survival of HCC patients. In addition, the effects of DDX55 in the promotion of HCC cell proliferation, migration, and invasion were determined ex vivo and in vivo. Mechanistically, we revealed that DDX55 could interact with BRD4 to form a transcriptional regulatory complex that positively regulated PIK3CA transcription. Following that, β‐catenin signaling was activated in a PI3K/Akt/GSK‐3β dependent manner, thus inducing cell cycle progression and epithelial–mesenchymal transition. Intriguingly, both DDX55 mRNA and protein were identified in the exosomes derived from HCC cells. Exosomal DDX55 was implicated in intercellular communication between HCC cells with high or low DDX55 levels and between HCC cells and endothelial cells, thereby promoting the malignant phenotype of HCC cells and angiogenesis. In conclusion, DDX55 may be a valuable prognostic biomarker and therapeutic target in HCC.

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“…After lentivirus was collected, 8 μg/mL polybrene was chosen to infect A375 cell line, followed by the selection process using 2 μg/mL puromycin for more than 72 h. For detailed protocols, refer to the prior study. 44 …”

Section: Methodsmentioning

confidence: 99%

Erianin suppresses constitutive activation of MAPK signaling pathway by inhibition of CRAF and MEK1/2

Wang

Jing

et al. 2023

Sig Transduct Target Ther

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Constitutive activation of RAS-RAF-MEK-ERK signaling pathway (MAPK pathway) frequently occurs in many cancers harboring RAS or RAF oncogenic mutations. Because of the paradoxical activation induced by a single use of BRAF or MEK inhibitors, dual-target RAF and MEK treatment is thought to be a promising strategy. In this work, we evaluated erianin is a novel inhibitor of CRAF and MEK1/2 kinases, thus suppressing constitutive activation of the MAPK signaling pathway induced by BRAF V600E or RAS mutations. KinaseProfiler enzyme profiling, surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), cellular thermal shift assay, computational docking, and molecular dynamics simulations were utilized to screen and identify erianin binding to CRAF and MEK1/2. Kinase assay, luminescent ADP detection assay, and enzyme kinetics assay were investigated to identify the efficiency of erianin in CRAF and MEK1/2 kinase activity. Notably, erianin suppressed BRAF V600E or RAS mutant melanoma and colorectal cancer cell by inhibiting MEK1/2 and CRAF but not BRAF kinase activity. Moreover, erianin attenuated melanoma and colorectal cancer in vivo. Overall, we provide a promising leading compound for BRAF V600E or RAS mutant melanoma and colorectal cancer through dual targeting of CRAF and MEK1/2.

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BRD4 drives esophageal squamous cell carcinoma growth by promoting RCC2 expression

Cited by 22 publications

References 63 publications

The m6A reader IGF2BP3 promotes acute myeloid leukemia progression by enhancing RCC2 stability

The m6A reader IGF2BP3 promotes acute myeloid leukemia progression by enhancing RCC2 stability

DDX55 promotes hepatocellular carcinoma progression by interacting with BRD4 and participating in exosome‐mediated cell‐cell communication

Erianin suppresses constitutive activation of MAPK signaling pathway by inhibition of CRAF and MEK1/2

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