ACOT12-Dependent Alteration of Acetyl-CoA Drives Hepatocellular Carcinoma Metastasis by Epigenetic Induction of Epithelial-Mesenchymal Transition

Lü, Ming; Zhu, Wenwei; Wang, Xuan; Tang, Jinshan; Zhang, Kaili; Yu, Guangyang; Shao, Wenjun; Lin, Zhongxiao; Wang, Shenghao; Lu, Lu; Zhou, Jian; Wang, Lian-Xin; Jia, Hongyan; Dong, Qiongzhu; Chen, Jinhong; Lu, Jianzhong; Qin, Lun–Xiu

doi:10.1016/j.cmet.2018.12.019

Cited by 110 publications

(92 citation statements)

References 47 publications

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“…Thus, we reintroduced an engineered PTPN13 cDNA (coding sequence without the 3'untranslated region (3'-UTR)) that was not sensitive to shPTPN13 #4, and found that PTPN13 re-expression was a good way to test its antitumor effect. Finally, we found that reintroducing shOE-PTPN13 returned the increases in cell proliferation close to baseline levels in HCC cells, as other studies have shown [38,39]. In addition, PTPN13 has been widely suggested to have intrinsic phosphatase activity; however, this interaction was phosphatase-independent.…”

Section: Discussionsupporting

confidence: 79%

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Anti-oncogene PTPN13 inactivation by hepatitis B virus X protein counteracts IGF2BP1 to promote hepatocellular carcinoma progression

et al. 2020

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Hepatitis B x protein (HBx) affects cellular protein expression and participates in the tumorigenesis and progression of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Metabolic reprogramming contributed to the HCC development, but its role in HBV-related HCC remains largely unclear. Tyrosine-protein phosphatase nonreceptor type 13 (PTPN13) is a significant regulator in tumor development, however, its specific role in hepatocarcinogenesis remains to be explored. Here, we found that decreased PTPN13 expression was associated with HBV/HBx. Patients with low PTPN13 expression showed a poor prognosis. Functional assays revealed that PTPN13 inhibited proliferation and tumorigenesis in vitro and in vivo. Further mechanistic studies indicated that HBx inhibited PTPN13 expression by upregulating the expression of DNMT3A and interacting with DNMT3A. Furthermore, we found that DNMT3A bound to the PTPN13 promoter (−343 to −313 bp) in an epigenetically controlled manner associated with elevated DNA methylation and then inhibited PTPN13 transcription. In addition, we identified IGF2BP1 as a novel PTPN13-interacting gene and demonstrated that PTPN13 influences c-Myc expression by directly and competitively binding to IGF2BP1 to decrease the intracellular concentration of functional IGF2BP1. Overexpressing PTPN13 promoted c-Myc mRNA degradation independent of the protein tyrosine phosphatase (PTP) activity of PTPN13. Importantly, we discovered that the PTPN13-IGF2BP1-c-Myc axis was important for cancer cell growth through promoting metabolic reprogramming. We verified the significant negative correlations between PTPN13 expression and c-Myc, PSPH, and SLC7A1 expression in clinical HCC tissue samples. In summary, our findings demonstrate that PTPN13 is a novel regulator of HBV-related hepatocarcinogenesis and may play an important role in HCC. PTPN13 may serve as a prognostic marker and therapeutic target in HBV-related HCC patients.

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Section: Discussionsupporting

confidence: 79%

“…Here, we found that HBx downregulated PTPN13 expression in hepatoma cells. The DNA hypermethylation of CpG islands is a critical epigenetic change that occurs in several malignancies, including HCC [39]. Aberrant PTPN13 hypermethylation has been observed in HCC [22].…”

Section: Discussionmentioning

confidence: 99%

Anti-oncogene PTPN13 inactivation by hepatitis B virus X protein counteracts IGF2BP1 to promote hepatocellular carcinoma progression

et al. 2020

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“…Cytosolic and nuclear acetyl-CoA levels are maintained by four metabolic pathways: (1) direct synthesis from acetate and CoA via acetyl-CoA synthetase short-chain family (ACSS); (2) conversion from citrate to acetyl-CoA by ATP citrate lyase (ACLY); (3) its catabolism to acetate and CoA by acyl-CoA thioesterase (ACOT); and (4) irreversible carboxylation from Acetyl-CoA to malonyl-CoA by Acetyl-CoA carboxylase (ACC) [9]. Deregulation of acetyl-CoA has been reported in multiple cancers [23][24][25][26][27][28][29][30][31][32][33], and it contribute to malignant phenotypes.…”

Section: Acetyl-coamentioning

confidence: 99%

“…Increased Acetyl-CoA triggers metastasis by inducing histone acetylation, leading to an open chromatin permissive for gene expression. Acetyl-CoA was shown to be involved in hepatocellular carcinoma (HCC) metastasis [24]. ACOT12, which catabolizes acetyl-CoA, was silenced in HCC and associated with metastasis and poor prognosis [24].…”

Section: Acetyl-coamentioning

confidence: 99%

Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications

et al. 2020

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Tumor metastasis is the major cause of mortality from cancer. Metabolic rewiring and the metastatic cascade are highly intertwined, co-operating to promote multiple steps of cancer metastasis. Metabolites generated by cancer cells influence the metastatic cascade, encompassing epithelial-mesenchymal transition (EMT), survival of cancer cells in circulation, and metastatic colonization at distant sites. A variety of molecular mechanisms underlie the prometastatic effect of tumor-derived metabolites, such as epigenetic deregulation, induction of matrix metalloproteinases (MMPs), promotion of cancer stemness, and alleviation of oxidative stress. Conversely, metastatic signaling regulates expression and activity of rate-limiting metabolic enzymes to generate prometastatic metabolites thereby reinforcing the metastasis cascade. Understanding the complex interplay between metabolism and metastasis could unravel novel molecular targets, whose intervention could lead to improvements in the treatment of cancer. In this review, we summarized the recent discoveries involving metabolism and tumor metastasis, and emphasized the promising molecular targets, with an update on the development of small molecule or biologic inhibitors against these aberrant situations in cancer.

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“…Metabolites like lactate could act as a direct signal instructing CAFs to produce HGF for tumors to survive the killing effect of sorafenib [57]. Recent studies also report that lactate and acetyl-CoA could act as substrates for histone modifications that epigenetically promote EMT and M2 polarization under hypoxia [80,81]. On the other hand, metabolic enzymes also have a direct role in regulating transcription and translation in response to hypoxia and sorafenib treatment [45].…”

Section: Metabolic Changes and Post-translational Modificationsmentioning

confidence: 99%

The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma

et al. 2020

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A B S T R A C TIn most cases, sorafenib-resistant HCC cells exhibit significant mesenchymal phenotype and stemness features. In this context, tumor cells might undergo cell fate transition in response to sorafenib or other targeted drugs in the presence or absence of genetic mutations. Therefore, understanding the major characteristics of drug-resistant cells state helps to discover new treatments that overcome drug resistance. To note, little is known about the metabolic or microenvironmental aspects of the certain tumor cell states beyond the genome. This review mainly focuses on the underlying mechanisms of acquired sorafenib resistance based on CSCs and EMT models, which explain tumor heterogeneity and have been considered the major cause of secondary sorafenib resistance. In particular, it discusses how the tumor microenvironment and tumor metabolism regulate cell stemness, mesenchymal state, and sorafenib resistance through epigenetic regulations, and provides reliable targets that might have synergetic effect with sorafenib.

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ACOT12-Dependent Alteration of Acetyl-CoA Drives Hepatocellular Carcinoma Metastasis by Epigenetic Induction of Epithelial-Mesenchymal Transition

Cited by 110 publications

References 47 publications

Anti-oncogene PTPN13 inactivation by hepatitis B virus X protein counteracts IGF2BP1 to promote hepatocellular carcinoma progression

Anti-oncogene PTPN13 inactivation by hepatitis B virus X protein counteracts IGF2BP1 to promote hepatocellular carcinoma progression

Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications

The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma

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