Emerging role of FBXO22 in carcinogenesis

Cheng, Jiangting; Lin, Min; Chu, Maoping; Gong, Linghui; Bi, Yanli; Zhao, Yongchao

doi:10.1038/s41420-020-00303-0

Cited by 30 publications

(23 citation statements)

References 50 publications

(82 reference statements)

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“…Accumulating evidence suggested that FBXO22 exerts its oncogenic functions through mediating the ubiquitination and degradation of substrates in many human malignancies ( 40 ). However, the roles it plays in different tumors is inconsistent in physiological and pathological processes.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Expression, Prognostic Value, and Immune Infiltration for Ubiquitination-Related FBXOs in Pancreatic Ductal Adenocarcinoma

et al. 2022

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most refractory human malignancies. F-box only proteins (FBXO) are the core components of SKP1-cullin 1-F-box E3 ubiquitin ligase, which have been reported to play crucial roles in tumor initiation and progression via ubiquitination-mediated proteasomal degradation. However, the clinical implications and biological functions of FBXOs in PDAC have not been fully clarified. Herein we perform a comprehensive analysis for the clinical values and functional roles of FBXOs in PDAC using different public databases. We found that FBXO1 (CCNF), FBXO20 (LMO7), FBXO22, FBXO28, FBXO32, and FBXO45 (designated six-FBXOs) were robustly upregulated in PDAC tissues, which predicted an adverse prognosis of PDAC patients. There was a significant correlation between the expression levels of six-FBXOs and the clinicopathological features in PDAC. The transcriptional levels of six-FBXOs were subjected to the influence of promoter methylation levels. There were more than 40% genetic alterations and mutations of six-FBXOs, which affected the clinical outcome of PDAC patients. Furthermore, the expression of six-FBXOs was associated with immune infiltrations and activated status, including B cells, CD8+ T cells, CD4+ T cells, NK cells, macrophages, and dendritic cells. The functional prediction revealed that the six-FBXOs were involved in ubiquitination-related pathways and other vital signaling pathways, such as p53, PI3K/Akt, and Hippo pathway. Therefore, six-FBXOs are the promising prognostic biomarkers or potential targets for PDAC diagnosis and treatment.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Expression, Prognostic Value, and Immune Infiltration for Ubiquitination-Related FBXOs in Pancreatic Ductal Adenocarcinoma

et al. 2022

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“…Although many studies have shown that FBXO22 is involved in oncogenesis owing to its ubiquitination activity and the subsequent degradation of multiple proteins ( 2 ), the means by which FBXO22 affects tumor growth by regulating substrate protein levels was largely unknown. Thus, we identified 23 FBXO22-binding proteins using the STRING database and literature search; these were all significantly enriched in cell cycle-negative regulation and ubiquitination pathways.…”

Section: Discussionmentioning

confidence: 99%

“…F-Box only protein 22 (FBXO22), a PTM regulator, is a member of the F-box protein family with E3 ligase activity ( 1 ). Recently, FBXO22 has shown to mediate ubiquitination of multiple proteins and has been linked to tumorigenesis ( 2 ). FBXO22 is involved in cell development and differentiation, including in cancer, by controlling the stability of lysine demethylase 4A (KDM4A) ( 3 ); FBXO22 ubiquitylates p53 and forms a complex with KDM4A to regulate cellular senescence ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

Pan-Cancer Analyses Reveal Oncogenic Role and Prognostic Value of F-Box Only Protein 22

Chen

Yan

et al. 2022

Front. Oncol.

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The F-box protein 22 (FBXO22), an F-box E3 ligase, has been identified to be critically involved in carcinogenesis. However, a systematic assessment of the role of FBXO22 across human cancers is lacking. Here, we performed a pan-cancer analysis to explore the role of FBXO22 in 33 cancer types using multiomic data from The Cancer Genome Atlas (TCGA). First, we found that high FBXO22 expression in multiple cancers was closely associated with poor overall survival and relapse-free survival. Next, we identified ten proteins that interact with FBXO22 and 13 of its target substrates using the STRING database and a literature search to explore the regulatory role of FBXO22 in tumorigenesis. Genes encoding these proteins were found to be significantly enriched in cell cycle negative regulation and ubiquitination pathways. This was confirmed in nonsmall cell lung cancer A549 cells, where FBXO22 overexpression enhanced cyclin-dependent kinase 4 (CDK4) protein levels and promoted cell proliferation. Similarly, overexpression or interference of FBXO22 changed the protein level of one of its substrates, PTEN. Additionally, we found that FBXO22 mutations were accompanied by altered substrate expression, especially in uterine corpus endometrial carcinoma and lung adenocarcinoma; endometrial carcinoma patients with FBXO22 genetic alterations also had better overall and relapse-free survival. Notably, FBXO22 methylation levels were also decreased in most tumors, and hypomethylation of FBXO22 was associated with poor overall survival, relapse-free interval, and progression-free interval in pancreatic adenocarcinoma. Finally, we analyzed the correlation between the abundance of tumor infiltrating lymphocytes (TILs) and FBXO22 expression, copy number variation, and methylation. Multiple algorithms revealed that high FBXO22 expression was associated with lower TIL levels, especially in lung adenocarcinoma, lung squamous cell carcinoma, and sarcoma. Taken together, our findings demonstrate that FBXO22 degrades tumor suppressor genes by ubiquitination and inhibits the cell cycle to promote nonsmall cell lung cancer progression. Our study also provides a relatively comprehensive understanding of the oncogenic role of FBXO22 in different tumors.

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“…Several biological functions of FBXO22 in tumorigenesis have been determined in recent years. According to the different degradation target proteins of the FBXO22 complex, it plays a corresponding function in cells ( Cheng et al, 2020 ). FBXO22 promotes tumorigenesis by degrading nuclear PTEN ( Ge et al, 2020 ), promotes lung cancer by mediating the polyubiquitination with the inactivation of LKB1 ( Zhu et al, 2019 ) and Bach1 ( Lignitto et al, 2019 ), and promotes the development of hepatocellular carcinoma by regulating the ubiquitination and degradation of p21 ( Zhang et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

FBXO22 Promotes Growth and Metastasis and Inhibits Autophagy in Epithelial Ovarian Cancers via the MAPK/ERK Pathway

Zhao

Yong

et al. 2021

Front. Pharmacol.

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E3 ubiquitin ligase F-box only protein 22 (FBXO22), which targets the key regulators of cellular activities for ubiquitylation and degradation, plays an important role in tumorigenesis and metastasis. However, the function of FBXO22 in epithelial ovarian cancers has not been reported. This study aims to explore the biological function of FBXO22 in epithelial ovarian cancers progression and metastasis and its specific regulation mechanism. Immunohistochemistry analysis of tissue microarray was performed to evaluate the expression of FBXO22 in epithelial ovarian cancers patients. The proliferative ability of epithelial ovarian cancers cells was examined by the CCK8. The metastasis ability was detected by the wound healing assay, migration and invasion assays. Western blot was used to verify the relationship between FBXO22 expression and mitogen-activated protein kinase related proteins. Autophagic flux was detected by electron microscopy, mRFP-GFP-LC3 adenovirus, lysosomal tracker and western blot. For in vivo experiments, the effect of FBXO22 on epithelial ovarian cancers resistance was observed in a xenograft tumor model and a metastatic mice model. We found that FBXO22 expression was significantly increased in epithelial ovarian cancers tissues and was closely correlated with clinical pathological factors. As a result, we found that FBXO22 promoted the growth and metastasis, as well as inhibited the autophagy flux. In addition, we identified that FBXO22 performed these functions via the MAPK/ERK pathway. Our results first reported the function of FBXO22 in epithelial ovarian cancer and the correlation between FBXO22 and autophagy, suggesting FBXO22 as a novel target of epithelial ovarian cancers assessment and treatment.

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Emerging role of FBXO22 in carcinogenesis

Cited by 30 publications

References 50 publications

Comprehensive Analysis of Expression, Prognostic Value, and Immune Infiltration for Ubiquitination-Related FBXOs in Pancreatic Ductal Adenocarcinoma

Comprehensive Analysis of Expression, Prognostic Value, and Immune Infiltration for Ubiquitination-Related FBXOs in Pancreatic Ductal Adenocarcinoma

Pan-Cancer Analyses Reveal Oncogenic Role and Prognostic Value of F-Box Only Protein 22

FBXO22 Promotes Growth and Metastasis and Inhibits Autophagy in Epithelial Ovarian Cancers via the MAPK/ERK Pathway

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