FBXW7 and the Hallmarks of Cancer: Underlying Mechanisms and Prospective Strategies

Shen, Wenyue; Zhou, Quanwei; Peng, Chenxi; Zhang, Yingbo; Yuan, Qizhi; Zhu, Hecheng; Zhao, Ming; Jiang, Xingjun; Liu, Weidong; Ren, Chao

doi:10.3389/fonc.2022.880077

Cited by 15 publications

(22 citation statements)

References 229 publications

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“…Among these proteins, FBXW7 attracted the most attention ( Supplementary Figure S6C ). It is well known that FBXW7 serves as a tumor suppressor that promotes ubiquitination of a wide range of oncoproteins for proteasomal degradation, including mTOR ( 14 , 15 , 28 – 30 ). In line with this, our results also showed that FBXW7 overexpression significantly inhibited the proliferation and metastasis of HCC cells in vitro ( Supplementary Figure S7 ).…”

Section: Resultsmentioning

confidence: 99%

“…Many studies have shown that F-box proteins play indispensable roles in drug resistance ( 6 , 12 ). As the target protein of FBXO9, FBXW7 has been reported to increase chemosensitivity of HCC cells ( 14 , 31 ). Accordingly, we explored the effects of FBXO9 knockdown on the sensitivity of HCC cells to lenvatinib and sorafenib, the two first-line drugs for HCC therapy.…”

Section: Resultsmentioning

confidence: 99%

“…FBXW7 is a member of the F-box family. It is a well-established tumor inhibitor that targets a series of oncogenic proteins for degradation ( 14 , 15 , 32 ) and plays a powerful tumor suppressor role in a variety of tumors, including HCC ( 15 , 29 , 30 , 32 , 33 ). Some proteins have been reported to promote the degradation of FBXW7 through auto-ubiquitination, such as Pin1, ERK, PLK2, CSN6, and LSD1 ( 9 , 15 , 34 ).…”

Section: Discussionmentioning

confidence: 99%

“…However, primary and acquired drug resistance contribute to poor prognosis in cancer patients ( 12 , 26 ). Recently, F-box protein has been considered to play a pivotal role in the development of drug resistance ( 12 ), and previous studies have indicated that FBXW7 increases the chemosensitivity of HCC ( 14 , 31 ). Therefore, we investigated the effect of FBXO9 knockdown on drug resistance in HCC.…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, a series of studies have demonstrated that the expression of F-box proteins can be closely correlated with the occurrence, development, and drug resistance of tumors (12,13). For example, FBXL1 promotes tumorigenesis by facilitating the degradation of a series of tumor-suppressor proteins, such as such as p21 and p27 (12); FBXO22 degrades nuclear PTEN to promote tumorigenesis (10); and FBXW7 plays a tumorsuppressive role by degrading various cancer-promoting proteins such as mTOR, cyclin E, MCL-1, N-Myc, and SOX9 (12,14,15). However, less attention has been paid to FBXO9 (16).…”

Section: Introductionmentioning

confidence: 99%

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FBXO9 Mediates the Cancer-Promoting Effects of ZNF143 by Degrading FBXW7 and Facilitates Drug Resistance in Hepatocellular Carcinoma

et al. 2022

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F-box proteins are critical for malignancy because they control the turnover of key proteins that govern multiple cellular processes. F-box protein 9 (FBXO9) belongs to the F-box protein family and exhibits oncogenic properties in hematological malignancies. However, the function and molecular mechanism of FBXO9 in hepatocellular carcinoma (HCC) remain unclear. Here, we report that FBXO9 was remarkably overexpressed in HCC. Loss- and gain-of-function experiments showed that FBXO9 facilitates HCC cell proliferation and metastasis both in vitro and in vivo. Mechanistically, as a direct upstream transcription factor, FBXO9 is regulated by zinc finger protein 143 (ZNF143) and accelerates tumor growth and metastasis by targeting the F-box and WD repeat domain containing 7 (FBXW7) for ubiquitination and degradation. Additionally, we found that with FBXO9 knockdown, HCC cells were more sensitive to treatment with lenvatinib and sorafenib. In summary, our results demonstrate that a ZNF143-FBXO9-FBXW7 signaling regulatory axis may be involved in tumor progression in HCC, and suggest that FBXO9 could be a potential biomarker and therapeutic target for HCC.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

FBXO9 Mediates the Cancer-Promoting Effects of ZNF143 by Degrading FBXW7 and Facilitates Drug Resistance in Hepatocellular Carcinoma

et al. 2022

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Comprehensive characterization of PKHD1 mutation in human colon cancer

Han,

Gong,

et al. 2024

Cancer Medicine

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IntroductionThe PKHD1 (Polycystic Kidney and Hepatic Disease 1) gene is essential for producing fibrocystin or polyductin, which is crucial in various cellular functions. Mutations in PKHD1 have been found to be involved in the development and progression of colorectal cancer (CRC). Along with APC, TP53, and KRAS, PKHD1 is one of the most frequently mutated genes in CRC. PKHD1 expression is governed by the Wnt/PCP pathway, often dysregulated in CRC. Targeting this pathway, crucial for CRC progression, could unveil potential therapeutic strategies for colon cancer treatment.MethodsThis study examined an in‐house dataset of 3702 colon cancer samples, analyzing mutation landscapes, clinical features, tumor mutational burden (TMB), microsatellite instability (MSI), and chromosomal instability (CIN) score. For the survival analysis of PKHD1 patients, survival data of 436 colon adenocarcinoma samples were obtained from TCGA dataset. Additionally, 433 samples from TCGA with RNA‐seq data were used for the assessment of immune cell infiltration and gene set enrichment analysis.ResultsPolycystic Kidney and Hepatic Disease 1 mutation was detected in 424 colon cancer patients from our in‐house cohort and was associated with increased TMB, higher MSI, and lower CIN score. Importantly, within the TCGA dataset, PKHD1 mutations were identified as an independent prognostic factor, not merely correlated with established prognostic biomarkers, and were associated with poorer overall survival outcomes. In terms of immune response, these mutations correlated with increased enrichment scores for 12 immune cell types, including B cell plasma, macrophages, and naive CD4+ T cells. Additionally, interferon alpha and interferon‐gamma gene sets were significantly down‐regulated in patients with PKHD1 mutations (FDA q‐value < 0.1).ConclusionsOverall, these findings suggest that PKHD1 may be a potential biomarker for the prognosis of colon cancer and provide some insight for personalized immunotherapy.

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FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2

et al. 2023

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FBXW7 is a member of the F-box protein family, which functions as the substrate recognition component of the SCF E3 ubiquitin ligase. FBXW7 is a main tumor suppressor due to its ability to control proteasome-mediated degradation of several oncoproteins such as c-Jun, c-Myc, Cyclin E1, mTOR, and Notch1-IC. FBXW7 inactivation in human cancers results from a somatic mutation or downregulation of its protein levels. This work describes a novel regulatory mechanism for FBXW7 dependent on the serine/threonine protein kinase DYRK2. We show that DYRK2 interacts with and phosphorylates FBXW7 resulting in its proteasome-mediated degradation. DYRK2-dependent FBXW7 destabilization is independent of its ubiquitin ligase activity. The functional analysis demonstrates the existence of DYRK2-dependent regulatory mechanisms for key FBXW7 substrates. Finally, we provide evidence indicating that DYRK2-dependent regulation of FBXW7 protein accumulation contributes to cytotoxic effects in response to chemotherapy agents such as Doxorubicin or Paclitaxel in colorectal cancer cell lines and to BET inhibitors in T-cell acute lymphoblastic leukemia cell lines. Altogether, this work reveals a new regulatory axis, DYRK2/FBXW7, which provides an understanding of the role of these two proteins in tumor progression and DNA damage responses.

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FBXW7 and the Hallmarks of Cancer: Underlying Mechanisms and Prospective Strategies

Cited by 15 publications

References 229 publications

FBXO9 Mediates the Cancer-Promoting Effects of ZNF143 by Degrading FBXW7 and Facilitates Drug Resistance in Hepatocellular Carcinoma

FBXO9 Mediates the Cancer-Promoting Effects of ZNF143 by Degrading FBXW7 and Facilitates Drug Resistance in Hepatocellular Carcinoma

Comprehensive characterization of PKHD1 mutation in human colon cancer

FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2

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