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1.
J Cell Biol ; 223(2)2024 02 05.
Article in English | MEDLINE | ID: mdl-38095639

ABSTRACT

Metastasis is the main cause of colorectal cancer (CRC)-related death, and the 5-year relative survival rate for CRC patients with distant metastasis is only 14%. X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a zinc-rich protein belonging to the interferon (IFN)-induced gene family. Here, we report a metastasis-promoting role of XAF1 in CRC by acting as a novel adaptor of valosin-containing protein (VCP). XAF1 facilitates VCP-mediated deubiquitination of the E3 ligase RING finger protein 114 (RNF114), which promotes K48-linked ubiquitination and subsequent degradation of junction plakoglobin (JUP). The XAF1-VCP-RNF114-JUP axis is critical for the migration and metastasis of CRC cells. Moreover, we observe correlations between the protein levels of XAF1, RNF114, and JUP in clinical samples. Collectively, our findings reveal an oncogenic function of XAF1 in mCRC and suggest that the XAF1-VCP-RNF114-JUP axis is a potential therapeutic target for CRC treatment.


Subject(s)
Adaptor Proteins, Signal Transducing , Apoptosis Regulatory Proteins , Colorectal Neoplasms , Intracellular Signaling Peptides and Proteins , Humans , Adaptor Proteins, Signal Transducing/metabolism , Apoptosis , Apoptosis Regulatory Proteins/metabolism , Colorectal Neoplasms/genetics , gamma Catenin/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Neoplasm Proteins/metabolism , Valosin Containing Protein/genetics , Valosin Containing Protein/metabolism
3.
Cell Rep ; 42(4): 112340, 2023 04 25.
Article in English | MEDLINE | ID: mdl-37027301

ABSTRACT

Pancreatic progenitor cell differentiation and proliferation factor (PPDPF) has been reported to play a role in tumorigenesis. However, its function in hepatocellular carcinoma (HCC) remains poorly understood. In this study, we report that PPDPF is significantly downregulated in HCC and the decreased PPDPF expression indicates poor prognosis. In the dimethylnitrosamine (DEN)-induced HCC mouse model, hepatocyte-specific depletion of Ppdpf promotes hepatocarcinogenesis, and reintroduction of PPDPF into liver-specific Ppdpf knockout (LKO) mice inhibits the accelerated HCC development. Mechanistic study shows that PPDPF regulates nuclear factor κB (NF-κB) signaling through modulation of RIPK1 ubiquitination. PPDPF interacts with RIPK1 and facilitates K63-linked ubiquitination of RIPK1 via recruiting the E3 ligase TRIM21, which catalyzes K63-linked ubiquitination of RIPK1 at K140. In addition, liver-specific overexpression of PPDPF activates NF-κB signaling and attenuates apoptosis and compensatory proliferation in mice, which significantly suppresses HCC development. This work identifies PPDPF as a regulator of NF-κB signaling and provides a potential therapeutic candidate for HCC.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Animals , Mice , Carcinogenesis/genetics , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/pathology , NF-kappa B/metabolism , Ubiquitination
4.
Cell Death Differ ; 30(2): 383-396, 2023 02.
Article in English | MEDLINE | ID: mdl-36396719

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) has become a growing public health problem. However, the complicated pathogenesis of NAFLD contributes to the deficiency of effective clinical treatment. Here, we demonstrated that liver-specific loss of Arid2 induced hepatic steatosis and this progression could be exacerbated by HFD. Mechanistic study revealed that ARID2 repressed JAK2-STAT5-PPARγ signaling pathway by promoting the ubiquitination of JAK2, which was mediated by NEDD4L, a novel E3 ligase for JAK2. ChIP assay revealed that ARID2 recruited CARM1 to increase H3R17me2a level at the NEDD4L promoter and activated the transcription of NEDD4L. Moreover, inhibition of Jak2 by Fedratinib in liver-specific Arid2 knockout mice alleviated HFD-induced hepatic steatosis. Downregulation of ARID2 and the reverse correlation between ARID2 and JAK2 were also observed in clinical samples. Therefore, our study has revealed an important role of ARID2 in the development of NAFLD and provided a potential therapeutic strategy for NAFLD.


Subject(s)
Insulin Resistance , Non-alcoholic Fatty Liver Disease , Mice , Animals , Non-alcoholic Fatty Liver Disease/pathology , Liver/metabolism , Mice, Knockout , Transcription Factors/genetics , Transcription Factors/metabolism , Diet, High-Fat , Ubiquitination , Mice, Inbred C57BL
5.
Adv Sci (Weinh) ; 10(2): e2202448, 2023 01.
Article in English | MEDLINE | ID: mdl-36453576

ABSTRACT

The guanine nucleotide exchange factor (GEF) SOS1 catalyzes the exchange of GDP for GTP on RAS. However, regulation of the GEF activity remains elusive. Here, the authors report that PPDPF functions as an important regulator of SOS1. The expression of PPDPF is significantly increased in pancreatic ductal adenocarcinoma (PDAC), associated with poor prognosis and recurrence of PDAC patients. Overexpression of PPDPF promotes PDAC cell growth in vitro and in vivo, while PPDPF knockout exerts opposite effects. Pancreatic-specific deletion of PPDPF profoundly inhibits tumor development in KRASG12D -driven genetic mouse models of PDAC. PPDPF can bind GTP and transfer GTP to SOS1. Mutations of the GTP-binding sites severely impair the tumor-promoting effect of PPDPF. Consistently, mutations of the critical amino acids mediating SOS1-PPDPF interaction significantly impair the GEF activity of SOS1. Therefore, this study demonstrates a novel model of KRAS activation via PPDPF-SOS1 axis, and provides a promising therapeutic target for PDAC.


Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Animals , Mice , Carcinoma, Pancreatic Ductal/genetics , Guanine Nucleotide Exchange Factors/genetics , Guanine Nucleotide Exchange Factors/metabolism , Guanosine Triphosphate , Intracellular Signaling Peptides and Proteins , Pancreatic Neoplasms/genetics , Proto-Oncogene Proteins p21(ras)/genetics , SOS1 Protein , Pancreatic Neoplasms
6.
Oncogene ; 41(36): 4244-4256, 2022 09.
Article in English | MEDLINE | ID: mdl-35906391

ABSTRACT

Lung cancer is the most common malignancy and the leading cause of cancer death worldwide, and lung adenocarcinoma (LUAD) is the most prevalent subtype. Considering the emergence of resistance to therapies, it is urgent to develop more effective therapies to improve the prognosis. Here we reported that pancreatic progenitor cell differentiation and proliferation factor (PPDPF) deficiency inhibited LUAD development both in vitro and in vivo. Mechanistically, PPDPF induces hyperactive STAT3 by interfering STAT3-PTPN1 interaction. Activated STAT3 promoted BMPR2 transcription, which further inhibited apoptosis. Moreover, PPDPF reduced NK cell infiltration and activation to develop an immunosuppressive microenvironment, which was also mediated by STAT3. Furthermore, we identified that the expression of PPDPF was positively correlated with the malignant features of LUAD, as well as BMPR2 and p-STAT3 level in clinical samples. Therefore, our study suggests that PPDPF positively regulates BMPR2 expression and facilitates immune escape via regulating STAT3 activity, providing a potential therapy target for LUAD.


Subject(s)
Adenocarcinoma of Lung , Adenocarcinoma , Lung Neoplasms , Adenocarcinoma/pathology , Adenocarcinoma of Lung/pathology , Apoptosis/genetics , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Humans , Intracellular Signaling Peptides and Proteins , Killer Cells, Natural/metabolism , Lung Neoplasms/pathology , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Tumor Microenvironment
7.
Cell Mol Gastroenterol Hepatol ; 14(1): 101-127, 2022.
Article in English | MEDLINE | ID: mdl-35390516

ABSTRACT

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a highly heterogeneous solid tumor with high morbidity and mortality. AT-rich interaction domain 1A (ARID1A) accounts for up to 10% of mutations in liver cancer, however, its role in HCC remains controversial, and no targeted therapy has been established. METHODS: The expression of ARID1A in clinical samples was examined by Western blot and immunohistochemical staining. ARID1A was knocked out by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) in HCC cell lines, and the effects of glucose deprivation on cell viability, proliferation, and apoptosis were measured. Mass spectrometry analysis was used to find ARID1A-interacting proteins, and the result was verified by co-immunoprecipitation and Glutathione S Transferase (GST) pull-down. The regulation of ARID1A target gene USP9X was investigated by chromatin immunoprecipitation, Glutathione S Transferase (GST) pull-down, luciferase reporter assay, and so forth. Finally, drug treatments were performed to explore the therapeutic potential of the agents targeting ARID1A-deficient HCC in vitro and in vivo. RESULTS: Our study has shown that ARID1A loss protected cells from glucose deprivation-induced cell death. A mechanism study disclosed that AIRD1A recruited histone deacetylase 1 via its C-terminal region DUF3518 to the promoter of USP9X, resulting in down-regulation of USP9X and its target protein kinase AMP-activated catalytic subunit α2 (PRKAA2). ARID1A knockout and a 1989∗ truncation mutant in HCC abolished this effect, increased the levels of H3K9 and H3K27 acetylation at the USP9X promoter, and up-regulated the expression of USP9X and protein kinase AMP-activated catalytic subunit α2 (PRKAA2), which mediated the adaptation of tumor cells to glucose starvation. Compound C dramatically inhibited the growth of ARID1A-deficient tumors and prolongs the survival of tumor-bearing mice. CONCLUSIONS: HCC patients with ARID1A mutation may benefit from synthetic lethal therapy targeting the ubiquitin-specific peptidase 9 X-linked (USP9X)-adenosine 5'-monophosphate-activated protein kinase (AMPK) axis.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , AMP-Activated Protein Kinases , Adenosine Monophosphate , Animals , Carcinoma, Hepatocellular/pathology , Cell Proliferation/physiology , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Glucose , Glutathione Transferase , Humans , Liver Neoplasms/pathology , Mice , Transcription Factors/genetics , Transcription Factors/metabolism , Ubiquitin Thiolesterase/genetics
8.
Toxins (Basel) ; 13(11)2021 11 13.
Article in English | MEDLINE | ID: mdl-34822586

ABSTRACT

Ochratoxin A(OTA) is considered to be one of the most important contaminants of food and feed worldwide. The liver is one of key target organs for OTA to exert its toxic effects. Due to current lifestyle and diet, nonalcoholic fatty liver disease (NAFLD) has been the most common liver disease. To examine the potential effect of OTA on hepatic lipid metabolism and NAFLD, C57BL/6 male mice received 1 mg/kg OTA by gavage daily. Compared with controls, OTA increased lipid deposition and TG accumulation in mouse livers. In vitro OTA treatment also promoted lipid droplets accumulation in primary hepatocytes and HepG2 cells. Mechanistically, OTA prevented PPARγ degradation by reducing the interaction between PPARγ and its E3 ligase SIAH2, which led to activation of PPARγ signaling pathway. Furthermore, downregulation or inhibition of CD36, a known of PPARγ, alleviated OTA-induced lipid droplets deposition and TG accumulation. Therefore, OTA induces hepatic steatosis via PPARγ-CD36 axis, suggesting that OTA has an impact on liver lipid metabolism and may contribute to the development of metabolic diseases.


Subject(s)
Hepatocytes/drug effects , Lipid Metabolism/drug effects , Non-alcoholic Fatty Liver Disease/chemically induced , Ochratoxins/toxicity , Animals , CD36 Antigens/metabolism , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/physiopathology , Hep G2 Cells , Hepatocytes/pathology , Humans , Male , Mice , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/physiopathology , PPAR gamma/metabolism
9.
Oncogene ; 40(34): 5302-5313, 2021 08.
Article in English | MEDLINE | ID: mdl-34247189

ABSTRACT

The prognosis of hepatocellular carcinoma (HCC) remains unsatisfactory due to limited effective treatment options. In this work, we investigated the therapeutic efficacy of Terbinafine for HCC and the underlying mechanism. The influence of Terbinafine on cell growth, 3D spheroid formation, clonogenic survival, and protein synthesis was investigated in human HCC cell lines. Co-immunoprecipitation, immunofluorescence, and other techniques were employed to explore how Terbinafine exerts its anticancer effect. Subcutaneous tumorigenicity assay, orthotopic and patient-derived xenograft (PDX) HCC models were used to evaluate the anticancer effect of Terbinafine monotherapy and the combinatorial treatment with Terbinafine and sorafenib against HCC. The anticancer activity of Terbinafine was Squalene epoxidase (SQLE)-independent. Instead, Terbinafine robustly suppressed the proliferation of HCC cells by inhibiting mTORC1 signaling via activation of AMPK. Terbinafine alone or in combination with sorafenib delayed tumor progression and markedly prolonged the survival of tumor-bearing mice. The synergy between Terbinafine and sorafenib was due to concomitant inhibition of mTORC1 and induction of severe persistent DNA double-strand breaks (DSBs), which led to the delayed proliferation and accelerated cell death. Terbinafine showed promising anticancer efficacy in preclinical models of HCC and may serve as a potential therapeutic strategy for HCC.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , AMP-Activated Protein Kinases , Animals , Mice , Terbinafine
10.
Nat Commun ; 12(1): 3059, 2021 05 24.
Article in English | MEDLINE | ID: mdl-34031390

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease in the world, however, no drug treatment has been approved for this disease. Thus, it is urgent to find effective therapeutic targets for clinical intervention. In this study, we find that liver-specific knockout of PPDPF (PPDPF-LKO) leads to spontaneous fatty liver formation in a mouse model at 32 weeks of age on chow diets, which is enhanced by HFD. Mechanistic study reveals that PPDPF negatively regulates mTORC1-S6K-SREBP1 signaling. PPDPF interferes with the interaction between Raptor and CUL4B-DDB1, an E3 ligase complex, which prevents ubiquitination and activation of Raptor. Accordingly, liver-specific PPDPF overexpression effectively inhibits HFD-induced mTOR signaling activation and hepatic steatosis in mice. These results suggest that PPDPF is a regulator of mTORC1 signaling in lipid metabolism, and may be a potential therapeutic candidate for NAFLD.


Subject(s)
Fatty Liver/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Liver/metabolism , Signal Transduction/physiology , TOR Serine-Threonine Kinases/metabolism , Animals , Cullin Proteins/metabolism , DNA-Binding Proteins/metabolism , HEK293 Cells , Hep G2 Cells , Humans , Lipid Metabolism , Liver/pathology , Male , Mice , Mice, Knockout , Non-alcoholic Fatty Liver Disease/metabolism
11.
Proc Natl Acad Sci U S A ; 117(9): 4770-4780, 2020 03 03.
Article in English | MEDLINE | ID: mdl-32071245

ABSTRACT

Recurrence and metastasis remain the major obstacles to successful treatment of hepatocellular carcinoma (HCC). Chromatin remodeling factor ARID2 is commonly mutated in HCC, indicating its important role in cancer development. However, its role in HCC metastasis is largely elusive. In this study, we find that ARID2 expression is significantly decreased in metastatic HCC tissues, showing negative correlation with pathological grade, organ metastasis and positive association with survival of HCC patients. ARID2 inhibits migration and invasion of HCC cells in vitro and metastasis in vivo. Moreover, ARID2 knockout promotes pulmonary metastasis in different HCC mouse models. Mechanistic study reveals that ARID2 represses epithelial-mesenchymal transition (EMT) of HCC cells by recruiting DNMT1 to Snail promoter, which increases promoter methylation and inhibits Snail transcription. In addition, we discover that ARID2 mutants with disrupted C2H2 domain lose the metastasis suppressor function, exhibiting a positive association with HCC metastasis and poor prognosis. In conclusion, our study reveals the metastasis suppressor role as well as the underlying mechanism of ARID2 in HCC and provides a potential therapeutic target for ARID2-deficient HCC.


Subject(s)
Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Chromatin Assembly and Disassembly/physiology , DNA (Cytosine-5-)-Methyltransferase 1/metabolism , Liver Neoplasms/drug therapy , Neoplasm Metastasis/drug therapy , Transcription Factors/metabolism , Animals , CYS2-HIS2 Zinc Fingers , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Movement/drug effects , Disease Models, Animal , Epithelial-Mesenchymal Transition , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Mice , Mice, Knockout , Mutation , Neoplasm Metastasis/pathology , Transcription Factors/antagonists & inhibitors , Transcription Factors/genetics
12.
Cell Prolif ; 52(3): e12583, 2019 May.
Article in English | MEDLINE | ID: mdl-30793395

ABSTRACT

OBJECTIVES: Wnt1-inducible signalling pathway protein 3 (WISP3/CCN6) belongs to the CCN (CYR61/CTGF/NOV) family of proteins, dysregulation of this family contributed to the tumorigenicity of various tumours. In this study, we need to explore its role in hepatocellular carcinoma that remains largely elusive. MATERIALS AND METHODS: The expression of WISP3/CCN6 was analysed by qRT-PCR and Western blotting. Effects of WISP3 on proliferation and metastasis of HCC cells were examined, respectively, by MTT assay and Boyden Chamber. Roles of WISP3 on HCC tumour growth and metastatic ability in vivo were detected in nude mice. Related mechanism study was confirmed by immunofluorescence and Western blotting. RESULTS: The expression of WISP3 was significantly downregulated in HCC clinical samples and cell lines, and reversely correlated with the tumour size. Forced expression of WISP3 in HCC cells significantly suppressed cell growth and migration in vitro as well as tumour growth and metastatic seeding in vivo. In contrast, downregulation of WISP3 accelerated cell proliferation and migration, and promoted in vivo metastasis. Further study revealed that WISP3 inhibited the translocation of ß-catenin to the nucleus by activating glycogen synthase kinase-3ß (GSK3ß). Moreover, constitutively active ß-catenin blocked the suppressive effects of WISP3 on HCC. CONCLUSIONS: Our study showed that WISP3 suppressed the progression of HCC by negative regulation of ß-catenin/TCF/LEF signalling, providing WISP3 as a potential therapeutic candidate for HCC.


Subject(s)
CCN Intercellular Signaling Proteins/genetics , CCN Intercellular Signaling Proteins/metabolism , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Active Transport, Cell Nucleus , Animals , CCN Intercellular Signaling Proteins/antagonists & inhibitors , Cell Line, Tumor , Cell Movement , Cell Proliferation , Disease Progression , Down-Regulation , Gene Knockdown Techniques , Glycogen Synthase Kinase 3 beta/metabolism , Heterografts , Humans , Male , Mice , Mice, Nude , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Small Interfering/genetics , Signal Transduction , TCF Transcription Factors/metabolism , beta Catenin/metabolism
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