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

Wang, Zhenyu; Chen, Xiaoxia; Zhou, Lianer; Zhao, Xinge; Chen, Ge; Zhao, Fangyu; Xie, Haiyang; Chen, Taoyang; Tian, Hua; Li, Hong; Li, Jinjun

doi:10.3389/fonc.2022.930220

Cited by 4 publications

(9 citation statements)

References 36 publications

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“…Interestingly, in line with this finding, it has been reported that increased UBD levels in rectal cancer correspond to favorable treatment outcomes [49]. On the contrary, FBXO9 has been implicated in driving drug resistance in hepatocellular carcinoma [50]. This inconsistency is likely due to different cancer types, as FBXO9 was found to overexpress in hepatocellular carcinoma [50].…”

Section: Potential Mechanisms Underlying Ubiquitination-mediated Ov Riskmentioning

confidence: 64%

“…On the contrary, FBXO9 has been implicated in driving drug resistance in hepatocellular carcinoma [50]. This inconsistency is likely due to different cancer types, as FBXO9 was found to overexpress in hepatocellular carcinoma [50]. Therefore, it is reasonable to deduce that the activity of ubiquitination, marked by FBXO9 and UBD expression, enhances the responsiveness to a range of drugs.…”

Section: Potential Mechanisms Underlying Ubiquitination-mediated Ov Riskmentioning

confidence: 99%

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Identification of a Prognostic Signature for Ovarian Cancer Based on Ubiquitin-Related Genes Suggesting a Potential Role for FBXO9

Luo,

Wang,

Zhang

et al. 2023

Biomolecules

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Background: Ovarian cancer (OV) is associated with high mortality and poses challenges in diagnosis and prognosis prediction. Ubiquitin-related genes (UbRGs) are involved in the initiation and progression of cancers, but have still not been utilized for diagnosis and prognosis of OV. Methods: K48-linked ubiquitination in ovarian tissues from our OV and control cohort was assessed using immunohistochemistry. UbRGs, including ubiquitin and ubiquitin-like regulators, were screened based on the TCGA-OV and GTEx database. Univariate Cox regression analysis identified survival-associated UbRGs. A risk model was established using the LASSO regression and multivariate Cox regression analysis. The relationship between UbRGs and immune cell infiltration, tumor mutational burden, drug sensitivity, and immune checkpoint was determined using the CIBERSORT, ESTIMATE, and Maftools algorithms, based on the Genomics of Drug Sensitivity in Cancer and TCGA-OV databases. GEPIA2.0 was used to analyze the correlation between FBXO9/UBD and DNA damage repair-related genes. Finally, FBXO9 and UBD were accessed in tissues or cells using immunohistochemistry, qPCR, and Western blot. Results: We confirmed the crucial role for ubiquitination in OV as a significant decrease of K48-linked ubiquitination was observed in primary OV lesions. We identified a prognostic signature utilizing two specific UbRGs, FBXO9 and UBD. The risk score obtained from this signature accurately predicted the overall survival of TCGA-OV training dataset and GSE32062 validation dataset. Furthermore, this risk score also showed association with immunocyte infiltration and drug sensitivity, revealing potential mechanisms for ubiquitination mediated OV risk. In addition, FBXO9, but not UBD, was found to be downregulated in OV and positively correlated with DNA damage repair pathways, suggesting FBXO9 as a potential cancer suppressor, likely via facilitating DNA damage repair. Conclusions: We identified and validated a signature of UbRGs that accurately predicts the prognosis, offers valuable guidance for optimizing chemotherapy and targeted therapies, and suggests a potential role for FBXO9 in OV.

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Section: Potential Mechanisms Underlying Ubiquitination-mediated Ov Riskmentioning

confidence: 64%

Section: Potential Mechanisms Underlying Ubiquitination-mediated Ov Riskmentioning

confidence: 99%

Identification of a Prognostic Signature for Ovarian Cancer Based on Ubiquitin-Related Genes Suggesting a Potential Role for FBXO9

Luo,

Wang,

Zhang

et al. 2023

Biomolecules

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“…In addition, magnolol reverses degradation and ubiquitination levels of PPARγ conferred by FBXO9, suggesting that magnolol stabilizes PPARγ by interrupting the interaction of PPARγ and FBXO9. FBXO9, a member of the F-box protein family and a substrate recognition component of the S-phase kinase associated protein 1 (Skp1)-cullin-1-F-box (SCF) E3 ligase complex, has been reported to participate in several cellular processes [37][38][39]. FBXO9 plays a pivotal role in the proteasome-dependent degradation of its substrates, including F-box/WD repeat-containing protein 7 (FBXW7) [38], cellular tumor antigen p53 [39], and PPARγ [15].…”

Section: Discussionmentioning

confidence: 99%

“…FBXO9, a member of the F-box protein family and a substrate recognition component of the S-phase kinase associated protein 1 (Skp1)-cullin-1-F-box (SCF) E3 ligase complex, has been reported to participate in several cellular processes [37][38][39]. FBXO9 plays a pivotal role in the proteasome-dependent degradation of its substrates, including F-box/WD repeat-containing protein 7 (FBXW7) [38], cellular tumor antigen p53 [39], and PPARγ [15]. Lee et al identified FBXO9 as a repressor of adipogenesis in 3T3-L1 preadipocytes by destabilizing PPARγ [15].…”

Section: Discussionmentioning

confidence: 99%

Targeting peroxisome proliferator‐activated receptor γ proteasomal degradation by magnolol is a potential avenue for adipogenesis‐mediated metabolic homeostasis

Mei

Wang

et al. 2023

Obesity

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Objective Adipogenesis has been recognized as an attractive avenue for maintaining systemic homeostasis, with peroxisome proliferator‐activated receptor γ (PPARγ) showing predominant roles in this process. This study aims to identify promising drug candidates by targeting PPARγ for adipogenesis‐based metabolic homeostasis and to clarify the detailed mechanisms. Methods Molecular events contributing to adipogenesis were screened, which identified PPARγ as having the predominant role. Promising agents of adipogenesis agonism were screened using a PPARγ‐based luciferase reporter assay. The functional capacity and molecular mechanisms of magnolol were intensively examined using 3T3‐L1 preadipocytes and dietary models. Results This study found that F‐box only protein 9 (FBXO9)‐mediated lysine 11 (K11)‐linked ubiquitination and proteasomal degradation of PPARγ are critically required during adipogenesis and systemic homeostasis. Notably, magnolol was identified as a potent adipogenesis activator by stabilizing PPARγ. The pharmacological mechanisms investigations clarified that magnolol directly binds to PPARγ and markedly interrupts its interaction with FBXO9, leading to a decline in K11‐linked ubiquitination and proteasomal degradation of PPARγ. Clinically important, magnolol treatment significantly facilitates adipogenesis in vitro and in vivo. Conclusions The downregulation of K11‐linked ubiquitination of PPARγ caused by FBOX9 is essentially required for adipogenesis, while targeting PPARγ‐FBXO9 interaction provides a new avenue for the therapy of adipogenesis‐related metabolic disorder.

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“…FBXO9 (also known as FBX9 or NY-REN-57) belongs to the FBXO subfamily and is recognized as the substrate recognition subunit of the CRL1/SCF E3 ligase complex [ 33 ]. FBXO9 tends to exhibit oncogenic behavior in conditions such as multiple myeloma and hepatic carcinoma [ 34 , 35 ], although its role in various diseases (including cancer) is largely overlooked. However, it inhibits tumorigenesis in acute myeloid leukemia [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

Ubiquitin ligase subunit FBXO9 inhibits V-ATPase assembly and impedes lung cancer metastasis

Liu,

Chen,

et al. 2024

Exp Hematol Oncol

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Background The evolutionarily conserved protein FBXO9 acts as a substrate receptor for the SKP1-cullin-1-RBX1 ubiquitin ligase and is implicated in cancer, exhibiting either tumor-suppressive or oncogenic effects depending on the specific tumor type. However, their role in lung cancer metastasis remains unclear. Methods Lentiviral vectors carrying miRNA-based shRNA sequences for gene-specific knockdown were generated, and Lenti-CRISPR-Cas9 vectors containing gene-specific sgRNA sequences were designed. Gene overexpression was achieved using doxycycline-inducible lentiviral constructs, while gene knockdown or knockout cells were generated using shRNA and CRISPR-Cas9, respectively. Functional assays included migration, clonogenic survival assays, tumor sphere assays, and protein interaction studies using mass spectrometry, immunoprecipitation, and immunoblot analysis. Results This study identified FBXO9 as a crucial regulator that suppresses lung cancer cell migration, tumor sphere growth and restricts metastasis. We showed that FBXO9 facilitates the ubiquitination of the catalytic subunit A (ATP6V1A) of the Vacuolar-type H+-ATPase (V-ATPase), resulting in its interaction with the cytoplasmic chaperone HSPA8 and subsequent sequestration within the cytoplasm. This process hinders the assembly of functional V-ATPase, resulting in reduced vesicular acidification. In contrast, depletion of FBXO9 reduced ATP6V1A ubiquitination, resulting in increased V-ATPase assembly and vesicular acidification, thus promoting pro-metastatic Wnt signaling and metastasis of lung cancer cells. Furthermore, we demonstrated the effectiveness of inhibitors targeting V-ATPase in inhibiting lung cancer metastasis in a mouse model. Finally, we established a correlation between lower FBXO9 levels and poorer survival outcomes in patients with lung cancer. Conclusion These findings collectively elucidate the critical role of FBXO9 in regulating V-ATPase assembly and provide a molecular basis for FBXO9’s function in inhibiting lung cancer metastasis. This highlights the potential therapeutic opportunities of FBXO9 supplementation.

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

Cited by 4 publications

References 36 publications

Identification of a Prognostic Signature for Ovarian Cancer Based on Ubiquitin-Related Genes Suggesting a Potential Role for FBXO9

Identification of a Prognostic Signature for Ovarian Cancer Based on Ubiquitin-Related Genes Suggesting a Potential Role for FBXO9

Targeting peroxisome proliferator‐activated receptor γ proteasomal degradation by magnolol is a potential avenue for adipogenesis‐mediated metabolic homeostasis

Ubiquitin ligase subunit FBXO9 inhibits V-ATPase assembly and impedes lung cancer metastasis

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