<i>PDSS2</i>Deficiency Induces Hepatocarcinogenesis by Decreasing Mitochondrial Respiration and Reprogramming Glucose Metabolism

Li, Yan; Lin, Shuhai; Li, Lei; Zhi, Tian; Hu, Yumin; Ban, Xiaohua; Zeng, Tingting; Zhou, Ying; Zhu, Ying–Hui; Gao, Song; Deng, Wen; Zhang, Xiaoshi; Xie, Dan; Yuan, Yufeng; Huang, Peng; Li, Jinjun; Cai, Zongwei; Guan, Xin Yuan

doi:10.1158/0008-5472.can-17-2172

Cited by 32 publications

(37 citation statements)

References 43 publications

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“…Studies including our previous report demonstrated that PDSS2 is an important tumor suppressor in the development of malignant melanoma and gastric cancer [23,24]. In addition, we found that different variants of PDSS2 exist in HCC tumor tissues and cell lines [12]. Of note, one of the variants, PDSS2‐Del2, exhibits a different function than that of PDSS2.…”

Section: Discussionmentioning

confidence: 73%

“…The shRNA also targets PDSS2‐FL (full length). Considering the low ratio of PDSS2‐FL and loss of function of PDSS2‐FL in parental HCC cells [12], we believe that the knockdown of PDSS2‐Del2 accounts for most of the migration inhibition effect in PDSS2‐Del2 overexpressing HCC cells.…”

Section: Discussionmentioning

confidence: 99%

“…In our previous study, we showed that downregulation of prenyl diphosphate synthase subunit 2 (PDSS2), a key enzyme in coenzyme Q10 (CoQ10) synthesis, plays a key role in hepatocellular carcinogenesis [12]. The PDSS2 deficiency was found to induce a metabolic shift from mitochondrial respiration to aerobic glycolysis and chromosomal instability and ultimately to induce malignant transformation of the immortalized human liver cell line MIHA [12]. We also found a novel splicing variant of PDSS2: PDSS2‐Del2 (in which alternative splicing deleted exon 2) in HCC cells.…”

Section: Introductionmentioning

confidence: 99%

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PDSS2‐Del2, a new variant of PDSS2, promotes tumor cell metastasis and angiogenesis in hepatocellular carcinoma via activating NF‐κB

et al. 2020

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Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality worldwide. Our previous study identified a novel alternative splicing variant of prenyl diphosphate synthase subunit 2 (PDSS2) in HCC characterized by a deletion of exon 2, named PDSS2-Del2, which is devoid of the tumor-suppressive function of full-length PDSS2 (PDSS2-FL). To better understand the clinical significance of PDSS2-Del2, we performed a BaseScope assay on an HCC tissue microarray and found that positive staining for PDSS2-Del2 predicted a worse overall survival in patients with HCC (P=0.02). PDSS2-Del2 levels correlated significantly with microvessel counts in HCC tumor tissues. Importantly, PDSS2-Del2 overexpression functionally promoted HCC metastasis as demonstrated by in vitro and in vivo migration assays. In vivo assays also demonstrated that PDSS2-Del2 increased angiogenesis in xenografts. Furthermore, we discovered that elevated PDSS2-Del2 expression in HCC tumor cells decreased fumarate levels and activated canonical NF-κB pathway. The epithelial-to-mesenchymal transition (EMT) and WNT/β-catenin signaling pathways were also activated by overexpression. Dimethyl fumarate (DMF), a fumaric acid ester, effectively reduced the metastasis induced by PDSS2-Del2 as observed with in vivo spleen-liver metastasis animal experiments. Considering that DMF is a prescribed oral therapy for multiple sclerosis, it might be a potential treatment for metastasis of patients with HCC. Early clinical trials are needed to validate its potential in this context.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PDSS2‐Del2, a new variant of PDSS2, promotes tumor cell metastasis and angiogenesis in hepatocellular carcinoma via activating NF‐κB

et al. 2020

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“…Augmented glycolysis and the concomitant increase in glucose consumption by malignant tumors is used clinically to diagnose and monitor treatment responses of cancers by imaging the uptake of fluorine-18 fluorodeoxyglucose ( 18 F-FDG) with positron emission tomography (PET) 35 . Emerging evidences indicate that many cancers, including HCC, display an aerobic glycolytic phenotype, resulting in tumor progression and thereby affecting the clinical outcomes and clinicopathologic characteristics of cancer patients 36,37 . Despite the widespread appreciation and clinical application, how the Warburg effect is regulated in cancer remains largely unclear.…”

Section: Discussionmentioning

confidence: 99%

Monomethyltransferase SET8 facilitates hepatocellular carcinoma growth by enhancing aerobic glycolysis

Chen

Ding

et al. 2019

Cell Death Dis

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Hepatocellular carcinoma (HCC) is one of the most aggressive cancers worldwide. Despite such a public health importance, efficient therapeutic agents are still lacking for this malignancy. Most tumor cells use aerobic glycolysis to sustain anabolic growth, including HCC, and the preference of glycolysis often leads to a close association with poorer clinical outcomes. The histone methyltransferase SET8 plays crucial roles in controlling cell-cycle progression, transcription regulation, and tumorigenesis. However, it remains largely undefined whether SET8 affects the glucose metabolism in HCC. Here, we report that upregulation of SET8 is positively correlated with a poor survival rate in HCC patients. Both in vitro and in vivo studies revealed that SET8 deficiency conferred an impaired glucose metabolism phenotype and thus inhibited the progression of HCC tumors. By contrast, SET8 overexpression aggravated the glycolytic alterations and tumor progression. Mechanistically, SET8 directly binds to and inactivates KLF4, resulting in suppression of its downstream SIRT4. We also provided further evidence that mutations in SET8 failed to restrain the transactivation of SIRT4 by KLF4. Our data collectively uncover a novel mechanism of SET8 in mediating glycolytic metabolism in HCC cells and may provide a basis for targeting SET8 as a therapeutic strategy in HCC.

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“…Previous investigations clearly indicated that the expression levels of PDSS2 are remarkably downregulated in several type of malignant tumors compared with their normal counterparts, including non-small cell lung cancer, primary melanoblastoma, gastric cancer, and liver cancer [11,12,18,19]. Gain-of-function studies revealed that exogenous overexpression of PDSS2 prominently inhibits tumor cell growth and invasion, highly suggesting that PDSS2 might act as a novel potential tumor suppresser gene and serve as a potential therapeutic target for cancers.…”

Section: Discussionmentioning

confidence: 99%

Sp1 Mediates the Constitutive Expression and Repression of the PDSS2 Gene in Lung Cancer Cells

Chen

Wang

et al. 2019

Genes

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Prenyl diphosphate synthase subunit 2 (PDSS2) is the first key enzyme in the CoQ10 biosynthesis pathway, and contributes to various metabolic and nephritic diseases. It has been reported that PDSS2 is downregulated in several types of tumors and acts as a potential tumor suppressor gene to inhibit the proliferation and migration of cancer cells. However, the regulatory mechanism of PDSS2 expression remains elusive. In the present study, we first identified and characterized the PDSS2 promoter region. We established four different luciferase reporter constructs which mainly cover the 2 kb region upstream of the PDSS2 gene transcription initiation site. Series luciferase reporter assay demonstrated that all four constructs have prominent promoter activity, and the core promoter of PDSS2 is mainly located within the 202 bp region near its transcription initiation site. Transcription factor binding site analysis revealed that the PDSS2 promoter contains binding sites for canonical transcription factors such as Sp1 and GATA-1. Overexpression of Sp1 significantly inhibited PDSS2 promoter activity, as well as its endogenous expression, at both mRNA and protein levels in lung cancer cells. Site-directed mutagenesis assay further confirmed that the Sp1 binding sites are essential for proximal prompter activity of PDSS2. Consistently, a selective Sp1 inhibitor, mithramycin A, treatment repressed the PDSS2 promoter activity, as well as its endogenous expression. Chromatin immunoprecipitation (ChIP) assay revealed that Sp1 binds to the PDSS2 promoter in vivo. Of note, the expression of Sp1 and PDSS2 are negatively correlated, and higher Sp1 expression with low PDSS2 expression is significantly associated with poor prognosis in lung cancer. Taken together, our results strongly suggest the essential role of Sp1 in maintaining the basic constitutive expression of PDSS2, and the pathogenic implication of Sp1-mediated PDSS2 transcriptional repression in lung cancer cells.

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PDSS2Deficiency Induces Hepatocarcinogenesis by Decreasing Mitochondrial Respiration and Reprogramming Glucose Metabolism

Cited by 32 publications

References 43 publications

PDSS2‐Del2, a new variant of PDSS2, promotes tumor cell metastasis and angiogenesis in hepatocellular carcinoma via activating NF‐κB

PDSS2‐Del2, a new variant of PDSS2, promotes tumor cell metastasis and angiogenesis in hepatocellular carcinoma via activating NF‐κB

Monomethyltransferase SET8 facilitates hepatocellular carcinoma growth by enhancing aerobic glycolysis

Sp1 Mediates the Constitutive Expression and Repression of the PDSS2 Gene in Lung Cancer Cells

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