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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2018 | Research

Yes-associated protein (YAP) binds to HIF-1α and sustains HIF-1α protein stability to promote hepatocellular carcinoma cell glycolysis under hypoxic stress

Authors: Xiaodong Zhang, Yan Li, Yingbo Ma, Liang Yang, Tao Wang, Xin Meng, Zhihong Zong, Xun Sun, Xiangdong Hua, Hangyu Li

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

Abstract

Background

Hypoxia-inducible factor 1α (HIF-1α) is essential in hepatocellular carcinoma (HCC) glycolysis and progression. Yes-associated protein (YAP) is a powerful regulator and is overexpressed in many cancers, including HCC. The regulatory mechanism of YAP and HIF-1α in HCC glycolysis is unknown.

Methods

We detected YAP expression in 54 matched HCC tissues and the adjacent noncancerous tissues. The relationship between YAP mRNA expression and that of HIF-1α was analyzed using The Cancer Genome Atlas HCC tissue data. We cultured HepG2 and Huh7 HCC cells under normoxic (20% O₂) and hypoxic (1% O₂) conditions, and measured the lactate and glucose levels, migration and invasive capability, and the molecular mechanism of HCC cell glycolysis and progression.

Results

In this study, we detected YAP expression in 54 matched HCC tissues and the adjacent noncancerous tissues. We observed that hypoxia-induced YAP activation is crucial for accelerating HCC cell glycolysis. Hypoxia inhibited the Hippo signaling pathway and promoted YAP nuclear localization, and decreased phosphorylated YAP expression in HCC cells. YAP knockdown inhibited HCC cell glycolysis under hypoxic. Mechanistically, hypoxic stress in the HCC cells promoted YAP binding to HIF-1α in the nucleus and sustained HIF-1α protein stability to bind to PKM2 gene and directly activates PKM2 transcription to accelerate glycolysis.

Conclusions

Our findings describe a new regulatory mechanism of hypoxia-mediated HCC metabolism, and YAP might be a promising therapeutic target in HCC.

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Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–32. https://doi.org/10.3322/caac.21338.CrossRefPubMed

Zhang W, Sun B. Impact of age on the survival of patients with liver cancer: an analysis of 27,255 patients in the SEER database. Oncotarget. 2015;6:633–41. https://doi.org/10.18632/oncotarget.2719.CrossRefPubMedPubMedCentral

Chiu DK, Tse AP, Xu IM, Di Cui J, Lai RK, Li LL, et al. Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma. Nat Commun. 2017;8:517. https://doi.org/10.1038/s41467-017-00530-7.CrossRefPubMedPubMedCentral

Chen C, Lou T. Hypoxia inducible factors in hepatocellular carcinoma. Oncotarget. 2017;8:46691–703. https://doi.org/10.18632/oncotarget.17358.PubMedPubMedCentralCrossRef

Rankin EB, Nam JM, Giaccia AJ. Hypoxia: signaling the metastatic Cascade. Trends Cancer. 2016;2:295–304. https://doi.org/10.1016/j.trecan.2016.05.006.CrossRefPubMedPubMedCentral

Fan Q, Yang L, Zhang X, Ma Y, Li Y, Li H, et al. Autophagy promotes metastasis and glycolysis by upregulating MCT1 expression and Wnt/beta-catenin signaling pathway activation in hepatocellular carcinoma cells. J Exp Clin Cancer Res. 2018;37:9. https://doi.org/10.1186/s13046-018-0673-y.CrossRefPubMedPubMedCentral

Azoitei N, Becher A, Steinestel K, Rouhi A, Diepold K, Genze F, et al. PKM2 promotes tumor angiogenesis by regulating HIF-1alpha through NF-kappaB activation. Mol Cancer. 2016;15:3. https://doi.org/10.1186/s12943-015-0490-2.CrossRefPubMedPubMedCentral

Cui XG, Han ZT, He SH, Wu XD, Chen TR, Shao CH, et al. HIF1/2alpha mediates hypoxia-induced LDHA expression in human pancreatic cancer cells. Oncotarget. 2017;8:24840–52. https://doi.org/10.18632/oncotarget.15266.PubMedPubMedCentralCrossRef

Zhang LF, Lou JT, Lu MH, Gao C, Zhao S, Li B, et al. Suppression of miR-199a maturation by HuR is crucial for hypoxia-induced glycolytic switch in hepatocellular carcinoma. EMBO J. 2015;34:2671–85. https://doi.org/10.15252/embj.201591803.CrossRefPubMedPubMedCentral

10.

Wan W, Peng K, Li M, Qin L, Tong Z, Yan J, et al. Histone demethylase JMJD1A promotes urinary bladder cancer progression by enhancing glycolysis through coactivation of hypoxia inducible factor 1alpha. Oncogene. 2017;36:3868–77. https://doi.org/10.1038/onc.2017.13.CrossRefPubMed

11.

Zhang Y, Ren YJ, Guo LC, Ji C, Hu J, Zhang HH, et al. Nucleus accumbens-associated protein-1 promotes glycolysis and survival of hypoxic tumor cells via the HDAC4-HIF-1alpha axis. Oncogene. 2017;36:4171–81. https://doi.org/10.1038/onc.2017.51.CrossRefPubMedPubMedCentral

12.

Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007;130:1120–33. https://doi.org/10.1016/j.cell.2007.07.019.CrossRefPubMedPubMedCentral

13.

Xu MZ, Yao TJ, Lee NP, Ng IO, Chan YT, Zender L, et al. Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer. 2009;115:4576–85. https://doi.org/10.1038/onc.2017.51.CrossRefPubMedPubMedCentral

14.

Perra A, Kowalik MA, Ghiso E, Ledda-Columbano GM, Di Tommaso L, Angioni MM, et al. YAP activation is an early event and a potential therapeutic target in liver cancer development. J Hepatol. 2014;61:1088–96. https://doi.org/10.1016/j.jhep.2014.06.033.CrossRefPubMed

15.

Yimlamai D, Fowl BH, Camargo FD. Emerging evidence on the role of the hippo/YAP pathway in liver physiology and cancer. J Hepatol. 2015;63:1491–501. https://doi.org/10.1016/j.jhep.2015.07.008.CrossRefPubMedPubMedCentral

16.

Li C, Wang S, Xing Z, Lin A, Liang K, Song J, et al. A ROR1-HER3-lncRNA signalling axis modulates the hippo-YAP pathway to regulate bone migration. Nat Cell Biol. 2017;19:106–19. https://doi.org/10.1038/ncb3464.CrossRefPubMedPubMedCentral

17.

Dai XY, Zhuang LH, Wang DD, Zhou TY, Chang LL, Gai RH, et al. Nuclear translocation and activation of YAP by hypoxia contributes to the chemoresistance of SN38 in hepatocellular carcinoma cells. Oncotarget. 2016;7:6933–47. https://doi.org/10.18632/oncotarget.6903.PubMedPubMedCentralCrossRef

18.

Wang Z, Liu P, Zhou X, Wang T, Feng X, Sun YP, et al. Endothelin promotes colorectal tumorigenesis by activating YAP/TAZ. Cancer Res. 2017;77:2413–23. https://doi.org/10.1158/0008-5472.CAN-16-3229.CrossRefPubMed

19.

Wang W, Xiao ZD, Li X, Aziz KE, Gan B, Johnson RL, Chen J. AMPK modulates hippo pathway activity to regulate energy homeostasis. Nat Cell Biol. 2015;17:490–9. https://doi.org/10.1038/ncb3113.CrossRefPubMedPubMedCentral

20.

DeRan M, Yang J, Shen CH, Peters EC, Fitamant J, Chan P, et al. Energy stress regulates hippo-YAP signaling involving AMPK-mediated regulation of angiomotin-like 1 protein. Cell Rep. 2014;9:495–503. https://doi.org/10.1016/j.celrep.2014.09.036.CrossRefPubMedPubMedCentral

21.

Enzo E, Santinon G, Pocaterra A, Aragona M, Bresolin S, Forcato M, et al. Aerobic glycolysis tunes YAP/TAZ transcriptional activity. EMBO J. 2015;34:1349–70. https://doi.org/10.15252/embj.201490379.CrossRefPubMedPubMedCentral

22.

Hu Y, Shin DJ, Pan H, Lin Z, Dreyfuss JM, Camargo FD, et al. YAP suppresses gluconeogenic gene expression through PGC1alpha. Hepatology. 2017;66:2029–41. https://doi.org/10.1002/hep.29373.CrossRefPubMed

23.

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45:W98–W102. https://doi.org/10.1093/nar/gkx247.CrossRefPubMedPubMedCentral

24.

Zhang X, Fan Q, Li Y, Yang Z, Yang L, Zong Z, et al. Transforming growth factor-beta1 suppresses hepatocellular carcinoma proliferation via activation of hippo signaling. Oncotarget. 2017;8:29785–94. https://doi.org/10.18632/oncotarget.14523.PubMedPubMedCentralCrossRef

25.

Shen S, Guo X, Yan H, Zhou D, Zhang L, Zhao B, et al. A miR-130a-YAP positive feedback loop promotes organ size and tumorigenesis. Cell Res. 2015;25:997–1012. https://doi.org/10.1038/cr.2015.98.CrossRefPubMedPubMedCentral

26.

Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50. https://doi.org/10.1073/pnas.0506580102.CrossRefPubMedPubMedCentral

27.

Wang H, Zhao L, Zhu LT, Wang Y, Pan D, Yao J, et al. Wogonin reverses hypoxia resistance of human colon cancer HCT116 cells via downregulation of HIF-1alpha and glycolysis, by inhibiting PI3K/Akt signaling pathway. Mol Carcinog. 2014;53:E107–18. https://doi.org/10.1002/mc.22052.CrossRefPubMed

28.

Luo W, Chang R, Zhong J, Pandey A, Semenza GL. Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression. Proc Natl Acad Sci U S A. 2012;109:E3367–76. https://doi.org/10.1073/pnas.1217394109.CrossRefPubMedPubMedCentral

29.

Wigerup C, Pahlman S, Bexell D. Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther. 2016;164:152–69. https://doi.org/10.1016/j.pharmthera.2016.04.009.CrossRefPubMed

30.

Pouyssegur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 2006;441:437–43. https://doi.org/10.1038/nature04871.CrossRefPubMed

31.

Zou J, Li P, Lu F, Liu N, Dai J, Ye J, et al. Notch1 is required for hypoxia-induced proliferation, invasion and chemoresistance of T-cell acute lymphoblastic leukemia cells. J Hematol Oncol. 2013;6:3. https://doi.org/10.1186/1756-8722-6-3.CrossRefPubMedPubMedCentral

32.

Hanna SC, Krishnan B, Bailey ST, Moschos SJ, Kuan PF, Shimamura T, et al. HIF1alpha and HIF2alpha independently activate SRC to promote melanoma metastases. J Clin Invest. 2013;123:2078–93. https://doi.org/10.1172/JCI66715.CrossRefPubMedPubMedCentral

33.

Vassilev A, Kaneko KJ, Shu H, Zhao Y, DePamphilis ML. TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/yes-associated protein localized in the cytoplasm. Genes Dev. 2001;15:1229–41. https://doi.org/10.1101/gad.888601.CrossRefPubMedPubMedCentral

34.

Zhao B, Ye X, Yu J, Li L, Li W, Li S, et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 2008;22:1962–71. https://doi.org/10.1101/gad.1664408.CrossRefPubMedPubMedCentral

35.

Tu K, Yang W, Li C, Zheng X, Lu Z, Guo C, et al. Fbxw7 is an independent prognostic marker and induces apoptosis and growth arrest by regulating YAP abundance in hepatocellular carcinoma. Mol Cancer. 2014;13:110. https://doi.org/10.1186/1476-4598-13-110.CrossRefPubMedPubMedCentral

36.

Steinhardt AA, Gayyed MF, Klein AP, Dong J, Maitra A, Pan D, et al. Expression of yes-associated protein in common solid tumors. Hum Pathol. 2008;39:1582–9. https://doi.org/10.1016/j.humpath.2008.04.012.CrossRefPubMedPubMedCentral

37.

Yu FX, Zhao B, Guan KL. Hippo pathway in organ size control, tissue homeostasis, and Cancer. Cell. 2015;163:811–28. https://doi.org/10.1016/j.cell.2015.10.044.CrossRefPubMedPubMedCentral

38.

Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer. 2015;15:73–9. https://doi.org/10.1038/nrc3876.CrossRefPubMedPubMedCentral

39.

Ban HS, Kim BK, Lee H, Kim HM, Harmalkar D, Nam M, et al. The novel hypoxia-inducible factor-1alpha inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth. Cell Death Dis. 2017;8:e2843. https://doi.org/10.1038/cddis.2017.235.CrossRefPubMedPubMedCentral

40.

Munksgaard Thoren M, Vaapil M, Staaf J, Planck M, Johansson ME, Mohlin S, Pahlman S. Myc-induced glutaminolysis bypasses HIF-driven glycolysis in hypoxic small cell lung carcinoma cells. Oncotarget. 2017;8:48983–95. https://doi.org/10.18632/oncotarget.16904.PubMedCrossRef

41.

Grandjean G, De Jong P, James B, Koh MY, Lemos R, Kingston J, et al. Definition of a novel feed-forward mechanism for glycolysis-HIF1alpha signaling in hypoxic tumors highlights aldolase a as a therapeutic target. Cancer Res. 2016;76:4259–69. https://doi.org/10.1158/0008-5472.CAN-16-0401.CrossRefPubMedPubMedCentral

42.

Lin L, Sabnis AJ, Chan E, Olivas V, Cade L, Pazarentzos E, et al. The hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat Genet. 2015;47:250–6. https://doi.org/10.1038/ng.3218.CrossRefPubMedPubMedCentral

43.

Azzolin L, Panciera T, Soligo S, Enzo E, Bicciato S, Dupont S, et al. YAP/TAZ incorporation in the beta-catenin destruction complex orchestrates the Wnt response. Cell. 2014;158:157–70. https://doi.org/10.1016/j.cell.2014.06.013.CrossRefPubMed

44.

Ma X, Wang H, Ji J, Xu W, Sun Y, Li W, et al. Hippo signaling promotes JNK-dependent cell migration. PNAS. 2017;114:1934–9. https://doi.org/10.1073/pnas.1621359114.CrossRefPubMed

45.

Ma B, Chen Y, Chen L, Cheng H, Mu C, Li J, et al. Hypoxia regulates hippo signalling through the SIAH2 ubiquitin E3 ligase. Nat Cell Biol. 2015;17:95–103. https://doi.org/10.1038/ncb3073.CrossRefPubMed

46.

Zhou TY, Zhuang LH, Hu Y, Zhou YL, Lin WK, Wang DD, et al. Inactivation of hypoxia-induced YAP by statins overcomes hypoxic resistance tosorafenib in hepatocellular carcinoma cells. Sci Rep. 2016;6:30483. https://doi.org/10.1038/srep30483.CrossRefPubMedPubMedCentral

47.

Yan L, Cai Q, Xu Y. Hypoxic conditions differentially regulate TAZ and YAP in cancer cells. Arch Biochem Biophys. 2014;562:31–6. https://doi.org/10.1016/j.abb.2014.07.024.CrossRefPubMedPubMedCentral

48.

Ma X, Zhang H, Xue X, Shah YM. Hypoxia-inducible factor 2alpha (HIF-2alpha) promotes colon cancer growth by potentiating yes-associated protein 1 (YAP1) activity. The J Biol Chem. 2017;292:17046–56. https://doi.org/10.1074/jbc.M117.805655.CrossRefPubMed

49.

Moroishi T, Park HW, Qin B, Chen Q, Meng Z, Plouffe SW, et al. A YAP/TAZ-induced feedback mechanism regulates hippo pathway homeostasis. Genes Dev. 2015;29:1271–84. https://doi.org/10.1101/gad.262816.115.CrossRefPubMedPubMedCentral

50.

Hansen CG, Moroishi T, Guan KL. YAP and TAZ: a nexus for hippo signaling and beyond. Trends Cell Biol. 2015;25:499–513. https://doi.org/10.1016/j.tcb.2015.05.002.CrossRefPubMedPubMedCentral

51.

Zanconato F, Forcato M, Battilana G, Azzolin L, Quaranta E, Bodega B, et al. Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat Cell Biol. 2015;17:1218–27. https://doi.org/10.1038/ncb3216.CrossRefPubMedPubMedCentral

Title: Yes-associated protein (YAP) binds to HIF-1α and sustains HIF-1α protein stability to promote hepatocellular carcinoma cell glycolysis under hypoxic stress
Authors: Xiaodong Zhang
Yan Li
Yingbo Ma
Liang Yang
Tao Wang
Xin Meng
Zhihong Zong
Xun Sun
Xiangdong Hua
Hangyu Li
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-018-0892-2

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