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      KDM5C Represses FASN-Mediated Lipid Metabolism to Exert Tumor Suppressor Activity in Intrahepatic Cholangiocarcinoma

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          Abstract

          Background: KDM5C is a histone H3K4-specific demethylase, which has multiple biological functions during development and disease. However, the role of KDM5C in intrahepatic cholangiocarcinoma (ICC) remains unknown.

          Methods: Expression levels of KDM5C in ICC patients were determined by qRT-PCR, western blotting and immunohistochemical assay. The functions of KDM5C in cell proliferation and invasion were determined in human ICC cells and mouse xenograft model using KDM5C overexpression and knockdown strategies in vivo. RNA-seq analysis was applied to investigate the transcriptional program of KDM5C. In addition, ChIP-qPCR was used to determine the regulation of FASN by KDM5C.

          Results: Here, we show that KDM5C was downregulated in human ICC, where its diminished expression was associated with poor prognosis. ICC cell proliferation and invasion were inhibited by KDM5C overexpression. Moreover, KDM5C suppressed ICC proliferation and metastasis in vivo. RNA-sequencing showed that KDM5C inhibits key signal pathways of cell proliferation, cell invasion and fatty acid metabolism. ChIP-qPCR revealed that overexpression of KDM5C led to the reduction of H3K4me3 on the promoter and the corresponding downregulation of the expression of FASN, which represents the major target gene of KDM5C to mediate the proliferation and invasion of ICC cells.

          Conclusions: Our results revealed the role of KDM5C as a novel tumor suppressor in ICC largely by repressing FASN-mediated lipid acid metabolism and thus KDM5C may contribute to the pathogenesis of ICC.

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          De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation.

          Evelien Rysman, Koen Brusselmans, Katryn Scheys … (2010)
          Activation of de novo lipogenesis in cancer cells is increasingly recognized as a hallmark of aggressive cancers and has been implicated in the production of membranes for rapid cell proliferation. In the current report, we provide evidence that this activation has a more profound role. Using a mass spectrometry-based phospholipid analysis approach, we show that clinical tumor tissues that display the lipogenic phenotype show an increase in the degree of lipid saturation compared with nonlipogenic tumors. Reversal of the lipogenic switch in cancer cells by treatment with the lipogenesis inhibitor soraphen A or by targeting lipogenic enzymes with small interfering RNA leads to a marked decrease in saturated and mono-unsaturated phospholipid species and increases the relative degree of polyunsaturation. Because polyunsaturated acyl chains are more susceptible to peroxidation, inhibition of lipogenesis increases the levels of peroxidation end products and renders cells more susceptible to oxidative stress-induced cell death. As saturated lipids pack more densely, modulation of lipogenesis also alters lateral and transversal membrane dynamics as revealed by diffusion of membrane-targeted green fluorescent protein and by the uptake and response to doxorubicin. These data show that shifting lipid acquisition from lipid uptake toward de novo lipogenesis dramatically changes membrane properties and protects cells from both endogenous and exogenous insults. These findings provide important new insights into the role of de novo lipogenesis in cancer cells, and they provide a rationale for the use of lipogenesis inhibitors as antineoplastic agents and as chemotherapeutic sensitizers. ©2010 AACR.
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            High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma.

            Xiao-Dong Zhu, Ju-Bo Zhang, Peng-Yuan Zhuang … (2008)
            To investigate prognostic values of the intratumoral and peritumoral expression of macrophage colony-stimulating factors (M-CSF) in hepatocellular carcinoma (HCC) patients after curative resection. Expression of M-CSF and density of macrophages (M Phi) were assessed by immunohistochemistry in tissue microarrays containing paired tumor and peritumoral liver tissue from 105 patients who had undergone hepatectomy for histologically proven HCC. Prognostic value of these and other clinicopathologic factors was evaluated. Neither intratumoral M-CSF nor M Phi density was associated with overall survival (OS) or disease-free survival (DFS). High peritumoral M-CSF and M Phi density, which correlated with large tumor size, presence of intrahepatic metastasis, and high TNM stage, were independent prognostic factors for both OS (P = .001 and P < .001, respectively) and DFS (P = .001 and P = .003, respectively) and affected incidence of early recurrence. In a small HCC subset, peritumoral M-CSF was also correlated with both OS and DFS (P = .038 and P = .001, respectively). The combination of peritumoral M-CSF and M Phi had a better power to predict the patients' death and disease recurrence (P < .001 for both). High peritumoral M-CSF and M Phi were associated with HCC progression, disease recurrence, and poor survival after hepatectomy, highlighting the importance of peritumoral tissue in the recurrence and metastasis of HCC. M-CSF and M Phi may be targets of postoperative adjuvant therapy.
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              SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism.

              Jongsook Kemper, Zachary Smith, Chang-Joo Kim … (2010)
              The SIRT1 deacetylase inhibits fat synthesis and stimulates fat oxidation in response to fasting, but the underlying mechanisms remain unclear. Here we report that SREBP-1c, a key lipogenic activator, is an in vivo target of SIRT1. SIRT1 interaction with SREBP-1c was increased during fasting and decreased upon feeding, and consistently, SREBP-1c acetylation levels were decreased during fasting in mouse liver. Acetylated SREBP-1c levels were also increased in HepG2 cells treated with insulin and glucose to mimic feeding conditions, and down-regulation of p300 by siRNA decreased the acetylation. Depletion of hepatic SIRT1 by adenoviral siRNA increased acetylation of SREBP-1c with increased lipogenic gene expression. Tandem mass spectrometry and mutagenesis studies revealed that SREBP-1c is acetylated by p300 at Lys-289 and Lys-309. Mechanistic studies using acetylation-defective mutants showed that SIRT1 deacetylates and inhibits SREBP-1c transactivation by decreasing its stability and its occupancy at the lipogenic genes. Remarkably, SREBP-1c acetylation levels were elevated in diet-induced obese mice, and hepatic overexpression of SIRT1 or treatment with resveratrol, a SIRT1 activator, daily for 1 week decreased acetylated SREBP-1c levels with beneficial functional outcomes. These results demonstrate an intriguing connection between elevated SREBP-1c acetylation and increased lipogenic gene expression, suggesting that abnormally elevated SREBP-1c acetylation increases SREBP-1c lipogenic activity in obese mice. Reducing acetylation of SREBP-1c by targeting SIRT1 may be useful for treating metabolic disorders, including fatty liver, obesity, and type II diabetes.
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Oncol
                Journal ID (iso-abbrev): Front Oncol
                Journal ID (publisher-id): Front. Oncol.
                Title: Frontiers in Oncology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 2234-943X
                Publication date (Electronic): 29 June 2020
                Publication date Collection: 2020
                Volume: 10
                Electronic Location Identifier: 1025
                Affiliations
                [1] 1Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education , Shanghai, China
                [2] 2Shanghai Ji Ai Genetics and IVF Institute, The Obstetrics and Gynecology Hospital of Fudan University , Shanghai, China
                [3] 3State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine , Shanghai, China
                Author notes

                Edited by: Yue Zhao, University of Cologne, Germany

                Reviewed by: Yan Wang, First Affiliated Hospital of Army Medical University, China; Wen-Lian Chen, Shanghai University of Traditional Chinese Medicine, China; Thomas MacVicar, Max Planck Institute for Biology of Ageing, Germany

                *Correspondence: Shan-he Yu yushanhe@ 123456shsmu.edu.cn

                This article was submitted to Cancer Metabolism, a section of the journal Frontiers in Oncology

                †These authors have contributed equally to this work

                Article
                DOI: 10.3389/fonc.2020.01025
                PMC ID: 7344276
                PubMed ID: 32714863
                SO-VID: 8f6241a0-5241-4bc3-ae1b-72f6153bc90d
                Copyright © Copyright © 2020 Zhang, Zhou, Xiao, Li, Guo, Wang, Yu and Ye.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 21 February 2020
                Date accepted : 22 May 2020
                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 57, Pages: 13, Words: 7064
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81502487
                Award ID: 81572301
                Award ID: 81802893
                Award ID: 81871924
                Award ID: 81900148
                Categories
                Subject: Oncology
                Subject: Original Research

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: kdm5c,fasn,cell proliferation,cell invasion,intrahepatic cholangiocarcinoma
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: kdm5c, fasn, cell proliferation, cell invasion, intrahepatic cholangiocarcinoma

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