SCFFBXW7/GSK3β-Mediated GFI1 Degradation Suppresses Proliferation of Gastric Cancer Cells

Kuai, Xiaoling; Li, Long; Chen, Ran; Wang, Kangjunjie; Chen, Min; Cui, Binghai; Zhang, Yuxue; Li, Junqiang; Zhu, Hongwen; Zhou, Hu; Huang, Jianfei; Qin, Jun; Wang, Zhiwei; Wei, Wenyi; Gao, Daming

doi:10.1158/0008-5472.can-18-4032

Cited by 20 publications

(14 citation statements)

References 42 publications

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“…6,7 Ubiquitination is one of the most important histone modifications and has been reported to be involved in the progress of GC frequently. 8,9 As a member of the deubiquitinating enzymes (DUBs) family, USP8 has been proved to be closely related to the occurrence and development of tumors, 10,11 including breast cancer, 12,13 lung cancer, 14 bladder cancer, 15 cervical cancer, 16 etc. USP8 was originally identified as a growth regulated ubiquitinspecific protease and is like many other DUBs characterized by its multidomain architecture.…”

Section: Introductionmentioning

confidence: 99%

<p>Down-Regulation of USP8 Suppresses HER-3 Positive Gastric Cancer Cells Proliferation</p>

Sun

Shen

Gao

et al. 2020

OTT

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Background: Ubiquitin specific peptidase 8 (USP8) has been reported to induce the degradation of several receptor tyrosine kinases such as epidermal growth factor receptor (EGFR), among which human epidermal growth factor receptor-3 (HER-3) is one of them. However, the role and functional mechanisms of USP8 and HER-3 in gastric cancer (GC) remain unknown. Objective: To explore the function and mechanism of USP8 and HER-3 in the progression of GC. Materials and Methods: Eighty-eight patients with histologically confirmed GC were recruited for this study. Tumor samples and GC cell lines were used to detect USP8 and HER-3 levels. MGC803 (HER-3 negative GC cell) was selected as the control group and NCI-N87, MKN-45 and AGS (HER-3 positive GC cells) as the experimental group. USP8i and si-RNA were then used to down-regulate USP8 in each group. Apoptosis and cell-cycle experiments were performed to detect the effects of USP8 on GC cells. Cytotoxicity Assay Kit (MTT) and colony formation assays were used to analyze cell proliferation. Cell migration and invasion ability were examined by wound healing. The expression of related mRNA and protein was detected by Western blot and quantitative real-time PCR (qRT-PCR). In vivo experiments were used to examine the effect of USP8 and HER-3. Results: Patients with high expression of USP8 or HER-3 tumors alone died earlier than those with low expression and the patients with both USP8 and HER-3 high expression had a shorter overall survival than those with the opposite pattern (both USP8 and HER-3 low expression). Down-regulation of USP8 inhibited cell proliferation and cell metastasis and also reduced the HER-3 expression. We also observed that down-regulation of USP8 inhibited the proliferation of GC cells which highly expressed HER-3. Moreover, downregulation of USP8 could promote the apoptosis of HER3-positive GC cells and inhibit the proliferation of them by affecting the cell-cycle. In vivo studies demonstrated that downregulation of USP8 inhibited HER-3 positive tumors growth. Conclusion: Down-regulation of USP8 inhibits HER-3 positive GC cells proliferation in vivo and in vitro, which indicate that USP8 represents a feasible choice as a therapeutic target for HER-3 positive GC cells.

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Section: Introductionmentioning

confidence: 99%

<p>Down-Regulation of USP8 Suppresses HER-3 Positive Gastric Cancer Cells Proliferation</p>

Sun

Shen

Gao

et al. 2020

OTT

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“…A number of c-Myc E3 ubiquitin ligases, including Fbxw7, Skp2, CHIP,FBX29, FBXO32, PirH2, TRIM32 and Truss have been reported to reduce c-Myc protein expression 19 , 20 . Interestingly, Gfi1 has been identified as a substrate of Fbxw7 25 . c-Myc degradation catalyzed by Fbxw7 is dependent on c-Myc threonine 58 26 .…”

Section: Resultsmentioning

confidence: 99%

“…The fact that the C-terminal ZF domains of Gfi1, which are required for its polyubiquitination and degradation 24 , are also required for c-Myc upregulation raises the possibility that Gfi1 and c-Myc might compete for binding to a common E3 ubiquitin ligase(s). Interestingly, both Gfi1 and c-Myc have been identified as the substrates of Fbxw7 25 . However, our data indicate that Fbxw7 may not play a key role in Gfi1-mediated regulation of c-Myc protein.…”

Section: Discussionmentioning

confidence: 99%

Gfi1 upregulates c-Myc expression and promotes c-Myc-driven cell proliferation

Zhang

Fan

2020

Sci Rep

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Gfi1 is a zinc-finger transcriptional repressor that plays an important role in hematopoiesis. When aberrantly activated, Gfi1 may function as a weak oncoprotein in the lymphoid system, but collaborates strongly with c-Myc in lymphomagenesis. The mechanism by which Gfi1 collaborates with c-Myc in lymphomagenesis is incompletely understood. We show here that Gfi1 augmented the expression of c-Myc protein in cells transfected with c-Myc expression constructs. The N-terminal SNAG domain and C-terminal ZF domains of Gfi1, but not its transcriptional repression and DNA binding activities, were required for c-Myc upregulation. We further show that Gfi1 overexpression led to reduced polyubiquitination and increased stability of c-Myc protein. Interestingly, the levels of endogenous c-Myc mRNA and protein were augmented upon Gfi1 overexpression, but reduced following Gfi1 knockdown or knockout, which was associated with a decline in the expression of c-Myc-activated target genes. Consistent with its role in the regulation of c-Myc expression, Gfi1 promoted Myc-driven cell cycle progression and proliferation. Together, these data reveal a novel mechanism by which Gfi1 augments the biological function of c-Myc and may have implications for understanding the functional collaboration between Gfi1 and c-Myc in lymphomagenesis.

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“…These targeted proteins all govern gastric tumorigenesis; for example, Brg1 promotes the metastasis of GC (92), RhoA has been implicated in gastric tumorigenesis (Fig. 1) (94), and GFI1 promotes GC cell proliferation as an oncoprotein (93). FBXW7 is also regulated by several upstream signaling molecules.…”

Section: C-terminus Of Hsp70-interacting Protein (Chip)mentioning

confidence: 99%

“…FBXW7 is a well-characterized SCF in GC and facilitates the destruction of oncogenic proteins, such as c-Myc, transforming protein RhoA (RhoA), transcription activator BRG1 (Brg1) and zinc-finger protein GFI-1 (GFI1) ( 90 – 93 ). These targeted proteins all govern gastric tumorigenesis; for example, Brg1 promotes the metastasis of GC ( 92 ), RhoA has been implicated in gastric tumorigenesis ( Fig.…”

Section: Structure and Function Of Ring-type E3 Ligases In Gcmentioning

confidence: 99%

Functional roles of E3 ubiquitin ligases in gastric cancer (Review)

Wang

Dai

et al. 2020

Oncol Lett

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To date, >650 E3 ubiquitin ligases have been described in humans, including >600 really interesting new genes (RINGs), 28 homologous to E6-associated protein C-terminus (HECTs) and several RING-in-between-RINGs. They are considered key regulators and therapeutic targets of many types of human cancers, including gastric cancer (GC). Among them, some RING and HECT E3 ligases are closely related to the proliferation, infiltration and prognosis of GC. During the past few years, abnormal expressions and functions of many E3 ligases have been identified in GC. However, the functional roles of E3 ligases in GC have not been fully elucidated. The present article focuses on the functional roles of E3 ligases related to the proteasome in GC. In this comprehensive review, the latest research progress on E3 ligases involved in GC and elaborate their structure, classification, functional roles and therapeutic value in GC was summarized. Finally, 30 E3 ligases that serve essential roles in regulating the development of GC were described. Some of these ligases may serve as oncogenes or tumor suppressors in GC, whereas the pathological mechanism of others needs further study; for example, constitutive photomorphogenic 1. In conclusion, the present review demonstrated that E3 ligases are crucial tumor regulatory factors and potential therapeutic targets in GC. Therefore, more studies should focus on the therapeutic targeting of E3 ligases in GC.

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SCFFBXW7/GSK3β-Mediated GFI1 Degradation Suppresses Proliferation of Gastric Cancer Cells

Cited by 20 publications

References 42 publications

<p>Down-Regulation of USP8 Suppresses HER-3 Positive Gastric Cancer Cells Proliferation</p>

<p>Down-Regulation of USP8 Suppresses HER-3 Positive Gastric Cancer Cells Proliferation</p>

Gfi1 upregulates c-Myc expression and promotes c-Myc-driven cell proliferation

Functional roles of E3 ubiquitin ligases in gastric cancer (Review)

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