FBXO31 sensitizes cancer stem cells‐like cells to cisplatin by promoting ferroptosis and facilitating proteasomal degradation of GPX4 in cholangiocarcinoma

RAB6A is a member of RAB GTPase family and plays an important role in the targeted transport of neurotrophic receptors and inflammatory cytokines. RAB6A‐mediated secretory pathway is involved in many physiological and pathological processes. Defects in RAB6A‐mediated secretory pathway may lead to the development of many diseases, including cancer. However, its role in cholangiocarcinoma (CCA) has not yet been revealed. We explored the regulatory role of RAB6A in the stem‐like subsets of CCA. We showed that RAB6A knockdown (KD) impedes cancer stem cells (CSCs) properties and epithelial−mesenchymal transition in vitro and that suppression of RAB6A inhibits tumor growth in vivo. We screened target cargos of RAB6A in CCA cells and identified a extracellular matrix component as the target cargo. RAB6A binds directly to OPN, and RAB6A KD suppressed OPN secretion and inhibited the interaction between OPN and αV integrin receptor. Moreover, RAB6A KD inhibited the AKT signaling pathway, which is a downstream effector of the integrin receptor signaling. In addition, shRNA targeting OPN blocked endogenous expression of OPN and consequently weakened CSCs properties in RAB6A‐formed spheres. Similarly, inhibitor of AKT signaling, MK2206 also impedes oncogenic function of RAB6A in the stem‐like subsets of CCA cells. In conclusion, our findings showed that RAB6A sustains CSCs phenotype maintenance by modulating the secretion of OPN and consequentially activating the downstream AKT signaling pathway. Targeting the RAB6A/OPN axis may be an effective strategy for CCA therapy.

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“…PLA was performed as previously described 14 . Briefly, tissue sections were dewaxed and subjected to antigen repair.…”

Section: Methodsmentioning

confidence: 99%

“…PLA was performed as previously described. 14 Briefly, tissue sections were dewaxed and subjected to antigen repair. CCA cells were fixed with 4% paraformaldehyde and treated with 0.1% Triton X-100.…”

Section: Proximity Ligation Assay (Pla)mentioning

confidence: 99%

RAB6A functions as a critical modulator of the stem‐like subsets in cholangiocarcinoma

Yang

Zhu

Zheng

et al. 2023

Molecular Carcinogenesis

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“…17 Previous research has demonstrated the significant role of ferroptosis in the prognostic prediction and treatment of CCA. [18][19][20] However, it is unclear whether GOLPH3 facilitates the progression of CCA and subsequently influences Next, the supernatant was replaced with fresh medium supplemented with 10% FBS, followed by selection of the stable lines. For GOLPH3 overexpression, the GOLPH3-expressing lentivirus transfected cells coexpressing GFP were selected using flow cytometry.…”

Section: Introductionmentioning

confidence: 99%

“…Morphologically, ferroptotic cells demonstrate shrunken mitochondria, a higher density of the mitochondrial membrane, and reduced or diminished mitochondrial cristae 17 . Previous research has demonstrated the significant role of ferroptosis in the prognostic prediction and treatment of CCA 18–20 . However, it is unclear whether GOLPH3 facilitates the progression of CCA and subsequently influences patient prognosis, and if so, what is the underlying molecular mechanism?…”

Section: Introductionmentioning

confidence: 99%

GOLPH3 promotes tumor malignancy via inhibition of ferroptosis by upregulating SLC7A11 in cholangiocarcinoma

Yin,

Liu,

Gao

et al. 2024

Molecular Carcinogenesis

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Golgi phosphoprotein 3 (GOLPH3) has been reported as an oncogene in various tumors; however, the role and function of GOLPH3 and its relevant molecular mechanism in cholangiocarcinoma (CCA) are unclear. Herein, GOLPH3 expression in CCA tissues was observed to be significantly higher than that in paired adjacent noncancerous tissues. Clinicopathological analysis showed that GOLPH3 expression correlated positively with the tumor‐node‐metastasis stage. In addition, GOLPH3 expression correlated inversely with the overall survival of patients with CCA. Multivariate analysis showed that GOLPH3 was an independent prognostic factor for patients with CCA. Transcriptome analysis (RNA sequencing) of GOLPH3 knockdown cells showed that the expression levels of nine ferroptosis‐related genes were significantly changed, indicating the important biological function of GOLPH3 in ferroptosis in CCA cells. Furthermore, GOLPH3 knockdown could significantly promote Erastin‐induced ferroptosis in vitro and suppress tumor growth in vivo. Overexpression of GOLPH3 had the opposite effect on this phenotype. Further studies revealed that GOLPH3 knockdown was significantly associated with a decrease in cysteine content, an accumulation of the lipid peroxidation product malondialdehyde, an increase in reactive oxygen species, and sensitized CCA cells to Erastin‐induced ferroptosis. Moreover, changes in GOLPH3 expression were found to be consistent with the expression of light chain subunit solute carrier family 7 member 11 (SLC7A11). Thus, our study suggested that GOLPH3 functions as an oncoprotein in CCA and may suppress ferroptosis by facilitating SLC7A11 expression, suggesting that GOLPH3 could serve as a therapeutic target for CCA treatment.

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“…, and MKK651 ; epithelial-mesenchymal transition (EMT) factors, Snail160 and Slug61 ; as well as ferroptosis inhibitor GPX462 . How it recognizes these substrates remains unclear.…”

mentioning

confidence: 99%

Impairment of FBXO31-mediated Ubiquitination of OGT Upregulates O-GlcNAcylation to Advance Endometrial Malignancy

Yuan,

Zhang,

Meng

et al. 2024

Preprint

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Aberrant O-GlcNAc cycling of the cancer proteome is a manifestation of its metabolic plasticity. As one of the most common cancer of the female genital tract associated with metabolic syndrome, endometrial cancer (EC) tissues often bear altered O-GlcNAcylation patterns. However, integration of O-GlcNAc status with existing histomorphologic and molecular subtypes of EC in large cohorts and identification of molecular modules controlling the O-GlcNAc homeostasis remain to be accomplished. Here we establish a positive correlation of O-GlcNAcylation with histologic grade of EC in a Chinese cohort containing 219 tumors and consolidate it in The Cancer Genome Atlas (TCGA) EC dataset. Higher O-GlcNAc level is associated with less pathological differentiation and poorer prognosis. Functionally, increasing O-GlcNAcylation promotes proliferation and stem-like cell properties in normal endometrial epithelial organoids (EE-Os), whereas decreasing O-GlcNAcylation limits the growth of endometrial cancer organoids (EC-Os). Using genome-wide CRISPR screen, we further identify that the F-box only protein 31 (FBXO31), whose loss of heterozygosity is frequently observed in cancer, regulates O-GlcNAc homeostasis. FBXO31 acts as a substrate receptor of the SCF ubiquitin ligase complex to ubiquitinate the O-GlcNAc transferase OGT. Loss of FBXO31 results in accumulation of OGT and upregulation of O-GlcNAcylation in EC. Our study highlights the O-GlcNAcylation as a useful stratification marker and potential therapeutic target for the advanced, poorly differentiated EC cases.

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FBXO31 sensitizes cancer stem cells‐like cells to cisplatin by promoting ferroptosis and facilitating proteasomal degradation of GPX4 in cholangiocarcinoma

Cited by 16 publications

References 45 publications

RAB6A functions as a critical modulator of the stem‐like subsets in cholangiocarcinoma

RAB6A functions as a critical modulator of the stem‐like subsets in cholangiocarcinoma

GOLPH3 promotes tumor malignancy via inhibition of ferroptosis by upregulating SLC7A11 in cholangiocarcinoma

Impairment of FBXO31-mediated Ubiquitination of OGT Upregulates O-GlcNAcylation to Advance Endometrial Malignancy

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