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DUSP4 maintains the survival and LSD1 protein stability in esophageal squamous cell carcinoma cells by inhibiting JNK signaling-dependent autophagy

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Abstract

DUSP4 is a biomarker of esophageal squamous cell carcinoma (ESCC), which is responsible for the prognosis in ESCC. However, the underlying mechanism of DUSP4-regulated ESCC carcinogenesis is unknown. As a negative regulator of JNK, DUSP4 can inhibit autophagy, which contributes to tumorigenesis. This study aimed to explore the role of autophagy in DUSP4-regulated ESCC carcinogenesis. Our results showed that DUSP4 overexpression inhibited autophagy and promoted LSD1 protein expression in ESCC cells, while DUSP4 silencing showed the opposite effects. However, DUSP4 overexpression and silencing did not affect LSD1 mRNA expression. But the regulatory ability of DUSP4 overexpression on autophagy, death level, and LSD1 protein was reversed by rapamycin. In addition, DUSP4 overexpression inhibited JNK and Bcl2 phosphorylation and the dissociation of Bcl2-Beclin1 complex, while DUSP4 silencing promoted JNK and Bcl2 phosphorylation. Moreover, the regulatory ability of DUSP4 overexpression on autophagy, death, and LSD1 protein was reversed by JNK activator anisomycin. The xenograft assays also showed that DUSP4 overexpression-promoted ESCC tumor growth in vivo and LC3II and LSD1 protein expression in tumor tissues were reversed by rapamycin or anisomycin. Overall, DUSP4 inhibits Bcl2-Beclin1-autophagy signal transduction through the negative regulation of JNK, thus suppressing autophagic death and the autophagic degradation of LSD1 in ESCC, by which DUSP4 promotes ESCC carcinogenesis.

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References

  • Abraham MC, Shaham S (2014) Death without caspases, caspases without death. Trends Cell Biol 14(4):184–193

    Article  Google Scholar 

  • Balko JM, Schwarz LJ, Bhola NE, Kurupi R, Owens P, Miller TW, Gómez H, Cook RS, Arteaga CL (2013) Activation of MAPK pathways due to DUSP4 loss promotes cancer stem cell-like phenotypes in basal-like breast cancer. Cancer Res 73(20):6346–6358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gaedcke J, Grade M, Jung K, Camps J, Jo P, Emons G, Gehoff A, Sax U, Schirmer M, Becker H, Beissbarth T, Ried T, Ghadimi BM (2010) Mutated KRAS results in overexpression of DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase, in rectal carcinomas. Genes Chromosomes Cancer 49(11):1024–1034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gröschl B, Bettstetter M, Giedl C, Woenckhaus M, Edmonston T, Hofstädter F, Dietmaier W (2013) Expression of the MAP kinase phosphatase DUSP4 is associated with microsatellite instability in colorectal cancer (CRC) and causes increased cell proliferation. Int J Cancer 132(7):1537–1546

    Article  PubMed  Google Scholar 

  • Han J, Ye S, Chen J, Wang K, Jin J, Zeng Z, Xue S (2021) Lysine-specific histone demethylase 1 promotes oncogenesis of the esophageal squamous cell carcinoma by upregulating DUSP4. Biochemistry (mosc) 86(12):1624–1634

    Article  CAS  PubMed  Google Scholar 

  • He H, Du Z, Lin J, Wu W, Yu Y (2021) DUSP4 inhibits autophagic cell death in PTC by inhibiting JNK-BCL2-Beclin1 signaling. Biochem Cell Biol 99(5):554–561

    Article  CAS  PubMed  Google Scholar 

  • Hou G, Zhao Q, Zhang M, Wang P, Ye H, Wang Y, Ren Y, Zhang J, Lu Z (2019) LSD1 regulates Notch and PI3K/Akt/mTOR pathways through binding the promoter regions of Notch target genes in esophageal squamous cell carcinoma. Onco Targets Ther 12:5215–5225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ke D, Ji L, Wang Y, Fu X, Chen J, Wang F, Zhao D, Xue Y, Lan X, Hou J (2019) JNK1 regulates RANKL-induced osteoclastogenesis via activation of a novel Bcl-2-Beclin1-autophagy pathway. FASEB J 33(10):11082–11095

    Article  CAS  PubMed  Google Scholar 

  • Kelkel M, Cerella C, Mack F, Schneider T, Jacob C, Schumacher M, Dicato M, Diederich M (2012) ROS-independent JNK activation and multisite phosphorylation of Bcl-2 link diallyl tetrasulfide-induced mitotic arrest to apoptosis. Carcinogenesis 33(11):2162–2171

    Article  CAS  PubMed  Google Scholar 

  • Keyse SM (2008) Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer Metastasis Rev 27(2):253–261

    Article  CAS  PubMed  Google Scholar 

  • Kutty RG, Talipov MR, Bongard RD, Lipinski RAJ, Sweeney NL, Sem DS, Rathore R, Ramchandran R (2017) Dual specificity phosphatase 5-substrate interaction: a mechanistic perspective. Compr Physiol 7(4):1449–1461

    Article  PubMed  Google Scholar 

  • Liu J, Lin A (2005) Role of JNK activation in apoptosis: a double-edged sword. Cell Res 15(1):36–42

    Article  PubMed  Google Scholar 

  • Liu S, Lin H, Wang D, Li Q, Luo H, Li G, Chen X, Li Y, Chen P, Zhai B, Wang W, Zhang R, Chen B, Zhang M, Han X, Li Q, Chen L, Liu Y, Chen X, Li G, Xiang Y, Duan T, Feng J, Lou J, Huang X, Zhang Q, Pan T, Yan L, Jin T, Zhang W, Zhuo L, Sun Y, Xie T, Sui X (2019) PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death. Signal Transduct Target Ther 4:53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu YW, Yang T, Zhao L, Ni Z, Yang N, He F, Dai SS (2016) Activation of Adenosine 2A receptor inhibits neutrophil apoptosis in an autophagy-dependent manner in mice with systemic inflammatory response syndrome. Sci Rep 6:33614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Low HB, Zhang Y (2016) Regulatory roles of MAPK phosphatases in cancer. Immune Netw 16(2):85–98

    Article  PubMed  PubMed Central  Google Scholar 

  • Lu Z, Ren Y, Zhang M, Fan T, Wang Y, Zhao Q, Liu HM, Zhao W, Hou G (2018) FLI-06 suppresses proliferation, induces apoptosis and cell cycle arrest by targeting LSD1 and Notch pathway in esophageal squamous cell carcinoma cells. Biomed Pharmacother 107:1370–1376

    Article  CAS  PubMed  Google Scholar 

  • Ma B, Shi R, Yang S, Zhou L, Qu N, Liao T, Wang Y, Wang Y, Ji Q (2016) DUSP4/MKP2 overexpression is associated with BRAF(V600E) mutation and aggressive behavior of papillary thyroid cancer. Onco Targets Ther 9:2255–2263

    CAS  PubMed  PubMed Central  Google Scholar 

  • Matsuda T, Ajiki W, Marugame T, Ioka A, Tsukuma H, Sobue T, Research Group of Population-Based Cancer Registries of Japan (2011) Population-based survival of cancer patients diagnosed between 1993 and 1999 in Japan: a chronological and international comparative study. Jpn J Clin Oncol. 41(1):40–51

    Article  PubMed  Google Scholar 

  • Nazim UM, Yin H, Park SY (2020) Neferine treatment enhances the TRAIL-induced apoptosis of human prostate cancer cells via autophagic flux and the JNK pathway. Int J Oncol 56(5):1152–1161

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ni Z, Wang B, Dai X, Ding W, Yang T, Li X, Lewin S, Xu L, Lian J, He F (2014) HCC cells with high levels of Bcl-2 are resistant to ABT-737 via activation of the ROS-JNK-autophagy pathway. Free Radic Biol Med 70:194–203

    Article  CAS  PubMed  Google Scholar 

  • Park KJ, Lee SH, Lee CH, Jang JY, Chung J, Kwon MH, Kim YS (2009) Upregulation of Beclin-1 expression and phosphorylation of Bcl-2 and p53 are involved in the JNK-mediated autophagic cell death. Biochem Biophys Res Commun 382(4):726–729

    Article  CAS  PubMed  Google Scholar 

  • Pattingre S, Bauvy C, Levade T, Levine B, Codogno P (2009) Ceramide-induced autophagy: to junk or to protect cells? Autophagy 5(4):558–560

    Article  CAS  PubMed  Google Scholar 

  • Pennathur A, Gibson MK, Jobe BA, Luketich JD (2013) Oesophageal carcinoma. Lancet 381(9864):400–412

    Article  PubMed  Google Scholar 

  • Prabhakar S, Asuthkar S, Lee W, Chigurupati S, Zakharian E, Tsung AJ, Velpula KK (2014) Targeting DUSPs in glioblastomas-wielding a double-edged sword? Cell Biol Int 38(2):145–153

    Article  CAS  PubMed  Google Scholar 

  • Qin X, Lu A, Ke M, Zhu W, Ye X, Wang G, Weng G (2020) DJ-1 inhibits autophagy activity of prostate cancer cells by repressing JNK-Bcl2-Beclin1 signaling. Cell Biol Int 44(4):937–946

    Article  CAS  PubMed  Google Scholar 

  • Siegel R, Naishadham D, Jemal A (2012) Cancer statistic. CA Cancer J Clin 62(1):10–29

    Article  PubMed  Google Scholar 

  • Umar SB, Fleischer DE (2018) Esophageal cancer: epidemiology, pathogenesis and prevention. Nat Clin Pract Gastroenterol Hepatol 5(9):517–526

    Article  Google Scholar 

  • Wang B, Zhao B, Pang LP, Zhao YD, Guo Q, Wang JW, Zheng YC, Zhang XH, Liu Y, Liu GY, Guo WG, Wang C, Li ZH, Mao XJ, Yu B, Ma LY, Liu HM (2017) LPE-1, an orally active pyrimidine derivative, inhibits growth and mobility of human esophageal cancers by targeting LSD1. Pharmacol Res 122:66–77

    Article  CAS  PubMed  Google Scholar 

  • Wang HY, Cheng Z, Malbon CC (2003) Overexpression of mitogen-activated protein kinase phosphatases MKP1, MKP2 in human breast cancer. Cancer Lett 191(2):229–237

    Article  CAS  PubMed  Google Scholar 

  • Wei Y, Pattingre S, Sinha S, Bassik M, Levine B (2008) JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell 30(6):678–688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu X, Gao F, Wang J, Tao L, Ye J, Ding L, Ji W, Chen X (2018) MiR-122-5p inhibits cell migration and invasion in gastric cancer by down-regulating DUSP4. Cancer Biol Ther 19(5):427–435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yip-Schneider MT, Lin A, Marshall MS (2001) Pancreatic tumor cells with mutant K-ras suppress ERK activity by MEK-dependent induction of MAP kinase phosphatase-2. Biochem Biophys Res Commun 280(4):992–997

    Article  CAS  PubMed  Google Scholar 

  • Zeng X, Zhu C, Zhu X (2021) DUSP4 promotes the carcinogenesis of CCRCC via negative regulation of autophagic death. Biosci Biotechnol Biochem 85(8):1839–1845

    Article  PubMed  Google Scholar 

  • Zhou N, Wei Z, Qi Z, Chen L (2021) Abscisic acid-induced autophagy selectively via MAPK/JNK signalling pathway in glioblastoma. Cell Mol Neurobiol 41(4):813–826

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by In-hospital project of The 900th Hospital of Joint Logistic Support Force, PLA (2020L03), Project of Fujian University of Traditional Chinese Medicine (XB2021185), Science & Technology Program of Jiangxi Health Commission (SKJP-220210990), and Focused Research and Development (R&D) program of Ganzhou Science and Technology Bureau (2020 (60)).

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Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, China

    Xinxin Liu

  2. Gannan Branch of National Clinical Research Center for Geriatrics Ganzhou 341000, Jiangxi, China

    Xinxin Liu

  3. Department of Digestive, The 900Th Hospital of Joint Logistic Support Force, PLA, Fuzhou, 350001, Fujian, China

    Zhou Ye

  4. Department of Thoracic Surgery, First Affiliated Hospital of Gannan Medical University, No. 3, Outangli, Xingannan Road, Zhanggong District, Ganzhou, 341000, Jiangxi, China

    Dingyu Rao & Zuxiong Zhang

  5. Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian, China

    Qianshun Chen & Zuxiong Zhang

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  1. Xinxin Liu
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  2. Zhou Ye
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  3. Dingyu Rao
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  4. Qianshun Chen
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Correspondence to Qianshun Chen or Zuxiong Zhang.

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Xinxin Liu and Zhou Ye are considered co-first authors.

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Liu, X., Ye, Z., Rao, D. et al. DUSP4 maintains the survival and LSD1 protein stability in esophageal squamous cell carcinoma cells by inhibiting JNK signaling-dependent autophagy. In Vitro Cell.Dev.Biol.-Animal 60, 115–122 (2024). https://doi.org/10.1007/s11626-023-00845-4

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  • DOI: https://doi.org/10.1007/s11626-023-00845-4

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