GOLPH3 Promotes Cancer Growth by Interacting With STIP1 and Regulating Telomerase Activity in Pancreatic Ductal Adenocarcinoma

Wang, Kebing; Jiang, Shuai; Huang, Anpei; Gao, Ying; Peng, Baogang; Li, Zhi; Ma, Wenbin; Songyang, Zhou; Zhang, Shihong; He, Mingbo; Li, Wen

doi:10.3389/fonc.2020.575358

Cited by 9 publications

(12 citation statements)

References 48 publications

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“…In glioma, GOLPH3 was found to facilitates the interaction of JAK2 and STAT3, leading to activation of the STAT3 pathway ( Wu et al, 2018 ). Previously, we reported that GOLPH3 interacted with STIP1, which then regulated telomerase activity and promoted tumor progression in pancreatic ductal adenocarcinama ( Wang et al, 2020 ). However, whether GOLPH3 regulates Golgi-to-nuclear protein trafficking is still not clear.…”

Section: Discussionmentioning

confidence: 99%

Golgi Phosphoprotein 3 Promotes Colon Cancer Cell Metastasis Through STAT3 and Integrin α3 Pathways

Huang

Wang

Cui

et al. 2022

Front. Mol. Biosci.

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Background: Golgi phosphoprotein 3 (GOLPH3) overexpression was recently reported to be associated with a poor clinical outcome in patients with colorectal cancer (CRC). However, the underlying molecular mechanism through which GOLPH3 promotes CRC metastasis remains poorly understood.Methods:In vitro genetic ablation of GOLPH3 was performed using siRNA transfection, and a stably overexpressed GOLPH3 colon cancer cell line was constructed using the lentivirus system. Cell invasion and migration assays were conducted with or without Matrigel. Immunoblotting, qRT-PCR, immunofluorescence and immunohistochemistry were utilized to study the expression level of GOLPH3, ZEB1, integrin α3 and phosphorylation level of STAT3, AKT/mTOR and Raf/MEK/ERK pathways. Co-immunoprecipitation was used to investigate the interaction between GOLPH3 and p-STAT3 (Tyr705) or total STAT3.Results: Overexpression of GOLPH3 was found in CRC tissues and colon cancer cell lines. Knockdown of GOLPH3 using siRNAs significantly suppressed the invasion and migration of HCT116 and HCT8 cells. In contrast, the overexpression of GOLPH3 promoted the migratory and invasive ability of colon cancer cells. The phosphorylation level of STAT3 as well as the protein and mRNA levels of ZEB1 and integrin α3, were significantly decreased after GOLPH3 knockdown. Moreover, Integrin α3 expression was correlated with GOLPH3 expression in CRC tissues. Co-immunoprecipitation assay revealed that GOLPH3 interacted with pSTAT3 (Tyr705) and total STAT3. Our further experiments suggested that GOLPH3 facilitated IL-6 induced STAT3 activation and subsequently induced transcription of integrin α3 and ZEB1, which promoted the metastasis and progression of CRC.Conclusion: Our current work demonstrates that GOLPH3 facilitates STAT3 activation and regulates the expression of EMT transcription factor ZEB1 and Integrin α3 in colon cancer cells. These findings indicate that GOLPH3 plays a critical role in CRC metastasis and might be a new therapeutic target for CRC treatment.

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Section: Discussionmentioning

confidence: 99%

Golgi Phosphoprotein 3 Promotes Colon Cancer Cell Metastasis Through STAT3 and Integrin α3 Pathways

Huang

Wang

Cui

et al. 2022

Front. Mol. Biosci.

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“…Since a cell cycle-specific kinase (Cdk1) phosphorylates Hop, it is proposed that Hop can differentially localize in cells depending on the cell cycle phases. This further raises the possibility of cell cycle phase-specific functions of Hop, an idea that is supported by the observation that a Hop knockdown or knockout in human cancer cells leads to a slowdown in G1 [ 27 – 29 ]. Interestingly, the phosphorylation sites of Hop are conserved between its murine and human orthologs.…”

Section: Discovery Expression and Localization Of Hopmentioning

confidence: 99%

The Hsp70–Hsp90 go-between Hop/Stip1/Sti1 is a proteostatic switch and may be a drug target in cancer and neurodegeneration

Bhattacharya

Picard

2021

Cell. Mol. Life Sci.

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The Hsp70 and Hsp90 molecular chaperone systems are critical regulators of protein homeostasis (proteostasis) in eukaryotes under normal and stressed conditions. The Hsp70 and Hsp90 systems physically and functionally interact to ensure cellular proteostasis. Co-chaperones interact with Hsp70 and Hsp90 to regulate and to promote their molecular chaperone functions. Mammalian Hop, also called Stip1, and its budding yeast ortholog Sti1 are eukaryote-specific co-chaperones, which have been thought to be essential for substrate (“client”) transfer from Hsp70 to Hsp90. Substrate transfer is facilitated by the ability of Hop to interact simultaneously with Hsp70 and Hsp90 as part of a ternary complex. Intriguingly, in prokaryotes, which lack a Hop ortholog, the Hsp70 and Hsp90 orthologs interact directly. Recent evidence shows that eukaryotic Hsp70 and Hsp90 can also form a prokaryote-like binary chaperone complex in the absence of Hop, and that this binary complex displays enhanced protein folding and anti-aggregation activities. The canonical Hsp70-Hop-Hsp90 ternary chaperone complex is essential for optimal maturation and stability of a small subset of clients, including the glucocorticoid receptor, the tyrosine kinase v-Src, and the 26S/30S proteasome. Whereas many cancers have increased levels of Hop, the levels of Hop decrease in the aging human brain. Since Hop is not essential in all eukaryotic cells and organisms, tuning Hop levels or activity might be beneficial for the treatment of cancer and neurodegeneration.

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“…GOLPH3 is highly expressed in many types of human cancer, including hepatocellular carcinoma, breast cancer, pancreatic ductal adenocarcinoma, and colon cancer, which it contributes to cancer progression. 10,[25][26][27] However, its expression and potential function in CCA remain unknown. The results of the present study revealed that GOLPH3 was highly expressed in CCA tissues and correlated significantly with the TNM clinical stage, especially T classification.…”

Section: Discussionmentioning

confidence: 99%

“…This finding is consistent with previously reported roles of GOLPH3 in various tumors. 10,26,27,35 Moreover, the knockdown of…”

Section: Discussionmentioning

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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GOLPH3 Promotes Cancer Growth by Interacting With STIP1 and Regulating Telomerase Activity in Pancreatic Ductal Adenocarcinoma

Cited by 9 publications

References 48 publications

Golgi Phosphoprotein 3 Promotes Colon Cancer Cell Metastasis Through STAT3 and Integrin α3 Pathways

Golgi Phosphoprotein 3 Promotes Colon Cancer Cell Metastasis Through STAT3 and Integrin α3 Pathways

The Hsp70–Hsp90 go-between Hop/Stip1/Sti1 is a proteostatic switch and may be a drug target in cancer and neurodegeneration

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

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