<i>Retracted:</i> The F‐box protein FBXO11 restrains hepatocellular carcinoma stemness via promotion of ubiquitin‐mediated degradation of Snail

Shao, Lijiang; Zhang, Xuehui; Qi, Yanfei

doi:10.1002/2211-5463.12933

Cited by 10 publications

(6 citation statements)

References 31 publications

(46 reference statements)

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“…It is also thought to play a role in maintenance of genome stability ( 12 ). Its function has mainly been studied in the context of different malignancies such as B-cell lymphoma ( 10 ), myelodysplastic syndrome ( 13 ), hepatocellular carcinoma ( 14 ), gastric cancer ( 15 ) and glioblastoma ( 16 ). The functional role of FBXO11 in neurodevelopmental disorders (NDDs) and neurodevelopment in general remains elusive.…”

Section: Introductionmentioning

confidence: 99%

De novo missense variants in FBXO11 alter its protein expression and subcellular localization

Gregor

Meerbrei

Gerstner

et al. 2021

Human Molecular Genetics

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Recently, we and others identified de novo FBXO11 variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs.

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Section: Introductionmentioning

confidence: 99%

De novo missense variants in FBXO11 alter its protein expression and subcellular localization

Gregor

Meerbrei

Gerstner

et al. 2021

Human Molecular Genetics

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“…Although the role of such MHC-II expression has not been elucidated, it has been proposed that MHC-II expression in tumors, called tumor-specific MHC-II (ts-MHC-II), plays a part of significant roles in cancer immunity in a variety of tumor types, and high expression of ts-MHC-II is associated with a favorable prognosis and responsiveness to immune checkpoint inhibitors ( 3 – 5 , 42 ). While tumor-related proteins such as BCL6, p53, SNAIL1, and BLIMP1 are known substrates of FBXO11, the role of FBXO11 in cancer is not yet clear ( 30 , 40 , 47 – 52 ). We examined the relationship between these FBXO11 substrates and survival of breast cancer patients and found that expression levels of BCL6 , TP53 , and SNAI1 had no effect on overall survival ( SI Appendix , Fig.…”

Section: Discussionmentioning

confidence: 99%

FBXO11 constitutes a major negative regulator of MHC class II through ubiquitin-dependent proteasomal degradation of CIITA

Kasuga

Ouda

Watanabe

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Major histocompatibility complex (MHC) class I and II molecules play critical roles in the activation and regulation of adaptive immunity through antigen presentation to CD8+ and CD4+ T cells, respectively. Strict regulation of MHC expression is critical for proper immune responses. CIITA (MHC class II transactivator), an NLR (nucleotide-binding domain, leucine-rich-repeat containing) protein, is a master regulator of MHC class II (MHC-II) gene transcription. Although it has been known that CIITA activity is regulated at the transcriptional and protein levels, the mechanism to determine CIITA protein level has not been elucidated. Here, we show that FBXO11 is a bona fide E3 ligase of CIITA and regulates CIITA protein level through ubiquitination-mediated degradation. A nonbiased proteomic approach for CIITA-binding protein identified FBXO11, a member of the Skp1–Cullin-1–F-box E3 ligase complex, as a binding partner of CIITA but not MHC class I transactivator, NLRC5. The cycloheximide chase assay showed that the half-life of CIITA is mainly regulated by FBXO11 via the ubiquitin–proteasome system. The expression of FBXO11 led to the reduced MHC-II at the promoter activity level, transcriptional level, and surface expression level through downregulation of CIITA. Moreover, human and mouse FBXO11 –deficient cells display increased levels of MHC-II and related genes. In normal and cancer tissues, FBXO11 expression level is negatively correlated with MHC-II. Interestingly, the expression of FBXO11 , along with CIITA , is associated with prognosis of cancer patients. Therefore, FBXO11 is a critical regulator to determine the level of MHC-II, and its expression may serve as a biomarker for cancer.

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“…The ubiquitination analysis was constructed under denaturing condition and the detailed procedure was referred to the previous work 22 . Briefly, recombinant proteins were incubated in 40 mM Tris‐HCl (pH 7.6), 50 mM NaCl, and 1 mM dithiothreitol with 100 ng of an E1 (UBE1; Boston Biochem), 250 ng of an E2 (UbcH5c; Boston Biochem), 5 μg of ubiquitin (sigma), and 2 mM ATP (Fermentas) for 3 hours.…”

Section: Methodsmentioning

confidence: 99%

“…The ubiquitination analysis was constructed under denaturing condition and the detailed procedure was referred to the previous work. 22 Briefly, recombinant proteins were incubated in 40 mM Tris-HCl…”

Section: Ubiquitination Analysismentioning

confidence: 99%

Carboxy terminus of HSP70‐interacting protein (CHIP) attenuates the stemness of thyroid cancer cells through decreasing OCT4 protein stability

Dang

et al. 2020

Environmental Toxicology

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Cancer cell stemness results in the occurrence and progression of tumors and Oct4 (octamer‐binding transcription factor) has been confirmed to be a critical contributor and marker of cancer cell stemness. Here, we aimed to explore the underlying mechanisms contributing to Oct4 protein stability, which is necessary for thyroid cancer (TC) cell stemness. We indicated that carboxy terminus of HSP70‐interacting protein (CHIP) protein was lowly expressed in TC tissues and cells, and positively correlated with the overall survival of TC patients. By analyzing the co‐expression network in TC tissues, we found that CHIP and Oct4 expression exhibited a negative correlation. Functional experiments showed that CHIP knockdown promoted the stemness of TC cells, while CHIP overexpression reduced the stemness of TC spheroids formed by TC cells, in which CHIP expression was significantly decreased. Furthermore, CHIP had no effect on TC cell viability. Mechanistic studies revealed that CHIP directly interacted with Oct4 protein and induced Oct4 ubiquitination, whereas a catalytic CHIP mutant (H260Q) did not. And CHIP regulated the stemness of TC cells in an Oct4‐dependent manner. Overall, this work indicates that the CHIP/Oct4 axis is essential for TC cell stemness.

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Retracted: The F‐box protein FBXO11 restrains hepatocellular carcinoma stemness via promotion of ubiquitin‐mediated degradation of Snail

Cited by 10 publications

References 31 publications

De novo missense variants in FBXO11 alter its protein expression and subcellular localization

De novo missense variants in FBXO11 alter its protein expression and subcellular localization

FBXO11 constitutes a major negative regulator of MHC class II through ubiquitin-dependent proteasomal degradation of CIITA

Carboxy terminus of HSP70‐interacting protein (CHIP) attenuates the stemness of thyroid cancer cells through decreasing OCT4 protein stability

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