Long Noncoding RNA MALAT1 regulates cancer glucose ... · 3/26/2019 · 1 Long Noncoding RNA MALAT1 regulates cancer glucose metabolism by enhancing mTOR-mediated translation of
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
1
Long Noncoding RNA MALAT1 regulates cancer glucose metabolism by enhancing
mTOR-mediated translation of TCF7L2
Pushkar Malakar1, Ilan Stein
2, Amijai Saragovi
2, Roni Winkler
3, Noam Stern-Ginossar
3, Michael
Berger2, Eli Pikarsky
2 and Rotem Karni
1*
1. Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel
Canada (IMRIC), Hebrew University-Hadassah Medical School, Jerusalem, 9112001 Israel,
2. The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research
Israel Canada (IMRIC) and Department of Pathology, Hebrew University–Hadassah Medical
School, Jerusalem, 9112001 Israel. 3. Department of Molecular Genetics, Weizmann Institute of
Science, 76100, Rehovot, Israel.
* Correspondence should be addressed to Rotem Karni, Department of Biochemistry and
Molecular Biology, Hebrew University-Hadassah Medical School, 9112001, Jerusalem, Israel.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
It is important to note that the true clinical implications of these results needs to be examined
further in human normal liver and HCC clinical samples.
Conclusion
Taken together, our data suggest that MALAT1 acts as a regulator of glucose metabolism in
HCC. Our results add insight to the mechanisms of cancer glucose metabolism and cancer
progression. The novel findings from the present study, together with the significant discoveries
from previous studies, place MALAT1 at the crossroad of cellular metabolism and
carcinogenesis (Fig. 7G). MALAT1 regulates the expression of TCF7L2 at the translational
level. TCF7L2 regulation by MALAT1 is through a mTORC1-dependent pathway via cap-
dependent translation. TCF7L2 plays an important role in MALAT1-induced tumorigenesis and
altered glucose metabolism in HCC development. These results point towards the fact that
knockdown of MALAT1 or reduction of TCF7L2 levels might serve as new strategies based on
tumor glucose metabolism for the treatment of HCC.
Acknowledgements
The authors wish to thank Dr. Zahava Siegfried for comments on the manuscript and Prof.
Fatima Gebauer (CRG, Barcelona) for the pSG5 Luc Plasmid. This study was supported in part
by Israel Science Foundation (ISF) (ISF Grant no' 1290/12 to R.K.),
References
1. Ulitsky I, Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell 2013;154(1):26-46. 2. Tsai M-C, Spitale RC, Chang HY. Long Intergenic Noncoding RNAs: New Links in Cancer
Progression. Cancer research 2011;71(1):3. 3. Arun G, Diermeier S, Akerman M, Chang K-C, Wilkinson JE, Hearn S, et al. Differentiation of
mammary tumors and reduction in metastasis upon Malat1 lncRNA loss. Genes & Development 2016;30(1):34-51.
4. Gutschner T, Hämmerle M, Diederichs S. MALAT1 — a paradigm for long noncoding RNA function in cancer. Journal of Molecular Medicine 2013;91(7):791-801.
5. Geisler S, Coller J. RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts. Nat Rev Mol Cell Biol 2013;14(11):699-712.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
6. Gutschner T, Hammerle M, Eissmann M, Hsu J, Kim Y, Hung G, et al. The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer research 2013;73(3):1180-9.
7. Hutchinson JN, Ensminger AW, Clemson CM, Lynch CR, Lawrence JB, Chess A. A screen for nuclear transcripts identifies two linked noncoding RNAs associated with SC35 splicing domains. BMC Genomics 2007;8(1):1-16.
8. Malakar P, Shilo A, Mogilevsky A, Stein I, Pikarsky E, Nevo Y, et al. Long Noncoding RNA MALAT1 Promotes Hepatocellular Carcinoma Development by SRSF1 Upregulation and mTOR Activation. Cancer research 2017;77(5):1155.
9. Sethi JK, Vidal-Puig A. Wnt signalling and the control of cellular metabolism. The Biochemical journal 2010;427(1):1-17.
10. Laplante M, Sabatini David M. mTOR Signaling in Growth Control and Disease. Cell 2012;149(2):274-93.
11. Hanahan D, Weinberg Robert A. Hallmarks of Cancer: The Next Generation. Cell 2011;144(5):646-74.
12. Warburg O, Wind F, Negelein E. THE METABOLISM OF TUMORS IN THE BODY. The Journal of General Physiology 1927;8(6):519-30.
13. Compan V, Pierredon S, Vanderperre B, Krznar P, Marchiq I, Zamboni N, et al. Monitoring Mitochondrial Pyruvate Carrier Activity in Real Time Using a BRET-Based Biosensor: Investigation of the Warburg Effect. Molecular Cell 2015;59(3):491-501.
14. Zhong X, Tian S, Zhang X, Diao X, Dong F, Yang J, et al. CUE domain‐containing protein 2 promotes the Warburg effect and tumorigenesis. EMBO reports 2017;18(5):809-25.
15. Dang CV, Le A, Gao P. MYC-induced Cancer Cell Energy Metabolism and Therapeutic Opportunities. Clinical cancer research : an official journal of the American Association for Cancer Research 2009;15(21):6479-83.
16. Shao W, Wang D, Chiang Y-T, Ip W, Zhu L, Xu F, et al. The Wnt Signaling Pathway Effector TCF7L2 Controls Gut and Brain Proglucagon Gene Expression and Glucose Homeostasis. Diabetes 2013;62(3):789.
17. Grant SFA, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nature Genetics 2006;38:320.
18. Karni R, Dor Y, Keshet E, Meyuhas O, Levitzki A. Activated pp60c-Src Leads to Elevated Hypoxia-inducible Factor (HIF)-1α Expression under Normoxia. Journal of Biological Chemistry 2002;277(45):42919-25.
19. Giakountis A, Moulos P, Zarkou V, Oikonomou C, Harokopos V, Hatzigeorgiou Artemis G, et al. A Positive Regulatory Loop between a Wnt-Regulated Non-coding RNA and ASCL2 Controls Intestinal Stem Cell Fate. Cell Reports;15(12):2588-96.
20. Yu T, Zhao Y, Hu Z, Li J, Chu D, Zhang J, et al. MetaLnc9 Facilitates Lung Cancer Metastasis via a PGK1-Activated AKT/mTOR Pathway. Cancer research 2017.
21. Hung C-L, Wang L-Y, Yu Y-L, Chen H-W, Srivastava S, Petrovics G, et al. A long noncoding RNA connects c-Myc to tumor metabolism. Proceedings of the National Academy of Sciences 2014;111(52):18697-702.
22. Zhao L, Ji G, Le X, Wang C, Xu L, Feng M, et al. Long Noncoding RNA LINC00092 Acts in Cancer-Associated Fibroblasts to Drive Glycolysis and Progression of Ovarian Cancer. Cancer research 2017;77(6):1369.
23. Rui L. Energy Metabolism in the Liver. Comprehensive Physiology 2014;4(1):177-97.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
24. Bian X-l, Chen H-z, Yang P-b, Li Y-p, Zhang F-n, Zhang J-y, et al. Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carboxykinase sumoylation. Nature Communications 2017;8:14420.
25. Hirata H, Sugimachi K, Komatsu H, Ueda M, Masuda T, Uchi R, et al. Decreased Expression of Fructose-1,6-bisphosphatase Associates with Glucose Metabolism and Tumor Progression in Hepatocellular Carcinoma. Cancer research 2016;76(11):3265.
26. Yang J, Wang C, Zhao F, Luo X, Qin M, Arunachalam E, et al. Loss of FBP1 facilitates aggressive features of hepatocellular carcinoma cells through the Warburg effect. Carcinogenesis 2017;38(2):134-43.
27. Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J, et al. Identification and Validation of Oncogenes in Liver Cancer Using an Integrative Oncogenomic Approach. Cell 2006;125(7):1253-67.
28. Karni R, de Stanchina E, Lowe SW, Sinha R, Mu D, Krainer AR. The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol 2007;14(3):185-93.
29. Singh S, Narayanan SP, Biswas K, Gupta A, Ahuja N, Yadav S, et al. Intragenic DNA methylation and BORIS-mediated cancer-specific splicing contribute to the Warburg effect. Proceedings of the National Academy of Sciences 2017;114(43):11440-45.
30. Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, et al. NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 2004;431:461.
31. Bercovich-Kinori A, Tai J, Gelbart IA, Shitrit A, Ben-Moshe S, Drori Y, et al. A systematic view on influenza induced host shutoff. eLife 2016;5.
32. Hay N. Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? Nature Reviews Cancer 2016;16:635.
33. Pusapati RV, Daemen A, Wilson C, Sandoval W, Gao M, Haley B, et al. mTORC1-Dependent Metabolic Reprogramming Underlies Escape from Glycolysis Addiction in Cancer Cells. Cancer cell 2016;29(4):548-62.
34. Adeva-Andany María M, Pérez-Felpete N, Fernández-Fernández C, Donapetry-García C, Pazos-García C. Liver glucose metabolism in humans. Bioscience Reports 2016;36(6):e00416.
35. Ma R, Zhang W, Tang K, Zhang H, Zhang Y, Li D, et al. Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma. Nature communications 2013;4:2508.
36. Oh K-J, Park J, Kim SS, Oh H, Choi CS, Koo S-H. TCF7L2 Modulates Glucose Homeostasis by Regulating CREB- and FoxO1-Dependent Transcriptional Pathway in the Liver. PLoS Genetics 2012;8(9):e1002986.
37. Ip W, Shao W, Song Z, Chen Z, Wheeler MB, Jin T. Liver-specific expression of dominant-negative transcription factor 7-like 2 causes progressive impairment in glucose homeostasis. Diabetes 2015;64(6):1923-32.
38. Ip W, Shao W, Chiang Y-tA, Jin T. The Wnt signaling pathway effector TCF7L2 is upregulated by insulin and represses hepatic gluconeogenesis. American Journal of Physiology - Endocrinology and Metabolism 2012;303(9):E1166-E76.
39. Jin T. Current Understanding on Role of the Wnt Signaling Pathway Effector TCF7L2 in Glucose Homeostasis. Endocrine reviews 2016;37(3):254-77.
40. Hinnebusch AG, Ivanov IP, Sonenberg N. Translational control by 5'-untranslated regions of eukaryotic mRNAs. Science 2016;352(6292):1413-6.
41. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes & Development 2004;18(16):1926-45.
42. Gingras A-C, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra MF, et al. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes & Development 1999;13(11):1422-37.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
43. Hsieh AC, Costa M, Zollo O, Davis C, Feldman ME, Testa JR, et al. Genetic Dissection of the Oncogenic mTOR Pathway Reveals Druggable Addiction to Translational Control via 4EBP-eIF4E. Cancer Cell 2010;17(3):249-61.
44. Cai W, Ye Q, She Q-B. Loss of 4E-BP1 function induces EMT and promotes cancer cell migration and invasion via cap-dependent translational activation of snail. Oncotarget 2014;5(15):6015-27.
45. Michlewski G, Sanford JR, Cáceres JF. The Splicing Factor SF2/ASF Regulates Translation Initiation by Enhancing Phosphorylation of 4E-BP1. Molecular Cell 2008;30(2):179-89.
46. Maslon MM, Heras SR, Bellora N, Eyras E, Caceres JF. The translational landscape of the splicing factor SRSF1 and its role in mitosis. eLife 2014:e02028.
47. Ip W, Shao W, Song Z, Chen Z, Wheeler MB, Jin T. Liver-Specific Expression of Dominant-Negative Transcription Factor 7-Like 2 Causes Progressive Impairment in Glucose Homeostasis. Diabetes 2015;64(6):1923-32.
48. Zhao DH, Hong JJ, Guo SY, Yang RL, Yuan J, Wen CJ, et al. Aberrant expression and function of TCF4 in the proliferation of hepatocellular carcinoma cell line BEL-7402. Cell Res 2004;14(1):74-80.
49. Sun Q, Hao Q, Prasanth KV. Nuclear Long Noncoding RNAs: Key Regulators of Gene Expression. Trends in Genetics 2018;34(2):142-57.
50. Tripathi V, Shen Z, Chakraborty A, Giri S, Freier SM, Wu X, et al. Long Noncoding RNA MALAT1 Controls Cell Cycle Progression by Regulating the Expression of Oncogenic Transcription Factor B-MYB. PLoS Genet 2013;9(3):e1003368.
51. Khan MW, Chakrabarti P. Gluconeogenesis combats cancer: opening new doors in cancer biology. Cell Death Dis 2015;6:e1872.
52. Mamane Y, Petroulakis E, LeBacquer O, Sonenberg N. mTOR, translation initiation and cancer. Oncogene 2006;25(48):6416-22.
53. Robichaud N, Sonenberg N, Ruggero D, Schneider RJ. Translational Control in Cancer. Cold Spring Harbor perspectives in biology 2018.
54. Gingras A-C, Kennedy SG, O’Leary MA, Sonenberg N, Hay N. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes & Development 1998;12(4):502-13.
55. Polunovsky VA, Bitterman PB. The Cap-Dependent Translation Apparatus Integrates and Amplifies Cancer Pathways. RNA Biology 2006;3(1):10-17.
56. Karni R, Hippo Y, Lowe SW, Krainer AR. The splicing-factor oncoprotein SF2/ASF activates mTORC1. Proceedings of the National Academy of Sciences 2008;105(40):15323-27.
Figure Legends
Figure 1: MALAT1 affects cancer glucose metabolism.
A. qRT-PCR of PHM-1 cells stably expressing hMALAT1 or an empty vector. B. Extracellular
lactate production was measured in cells described in (A) using a lactate assay kit (n=3). C.
PHM-1 cells over expressing MALAT1 knocked down for MALAT1 by siRNAs (siMALAT#1,
#2), were analyzed by qRT-PCR. D. Extracellular lactate production was measured in cells
described in (D) using a lactate assay kit (n=3). E. Schematic representation of the glycolytic and
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432
Published OnlineFirst March 26, 2019.Cancer Res Pushkar Malakar, Ilan Stein, Amijai Saragovi, et al. TCF7L2metabolism by enhancing mTOR-mediated translation of Long Noncoding RNA MALAT1 regulates cancer glucose
Updated version
10.1158/0008-5472.CAN-18-1432doi:
Access the most recent version of this article at:
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
Permissions
Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)
.http://cancerres.aacrjournals.org/content/early/2019/03/26/0008-5472.CAN-18-1432To request permission to re-use all or part of this article, use this link
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2019; DOI: 10.1158/0008-5472.CAN-18-1432