SUMOylation of HSP27 regulates PKM2 to promote esophageal squamous cell carcinoma progression

Zhang,Xiao; Liu,Tao; Zheng,Shutao; Liu,Qing; Shen,Tongxue; Han,Xiujuan; Zhang,Qiqi; Yang,Lifei; Lu,Xiaomei

doi:10.3892/or.2020.7711

SUMOylation of HSP27 regulates PKM2 to promote esophageal squamous cell carcinoma progression

Authors:
- Xiao Zhang
- Tao Liu
- Shutao Zheng
- Qing Liu
- Tongxue Shen
- Xiujuan Han
- Qiqi Zhang
- Lifei Yang
- Xiaomei Lu
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Affiliations: Clinical Medical Research Institute, First Afﬁliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830000, P.R. China, Health Management Center, Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830000, P.R. China, Cancer Hospital Affiliated of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830000, P.R. China
Published online on: July 31, 2020 https://doi.org/10.3892/or.2020.7711
Pages: 1355-1364
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

A previous proteomic screening of differentially expressed biomarkers between Kazakh patients with esophageal squamous cell carcinoma (ESCC) and normal adjacent tissues demonstrated that heat shock protein 27 (HSP27) and pyruvate kinase isoenzyme M2 (PKM2) were both highly expressed in ESCC samples compared with normal controls. However, the regulatory association between HSP27 and PKM2 in ESCC remains elusive. In the present study, immunohistochemistry and immunoblotting were adopted to examine the expression of HSP27, PKM2 and other relevant biomarkers involved in epithelial‑to‑mesenchymal transition in clinical tissue samples. The interactions between proteins were detected by co‑immunoprecipitation (Co‑IP) assay and further confirmed by immunofluorescence assay. The growth and motility of ESCC cells were examined by MTT, Transwell and wound healing assays. Overexpression of HSP27 was found to be significantly associated with T‑cell classification, lymph node metastasis and poor prognosis in ESCC. In addition, HSP27 expression was significantly correlated with PKM2 expression in ESCC specimens. Functionally, knockdown of HSP27 inhibited the growth and motility of ESCC cells. Moreover, HSP27 was found to directly interact with small ubiquitin‑related modified protein 2/3 (SUMO2/3) in ESCC cell lines, as evidenced by Co‑IP and laser confocal imaging. In addition, downregulation of HSP27 was shown to decrease PKM2 and E‑cadherin expression. Knockdown of SUMO2/3 was observed to reduce the expression of HSP27, PKM2 and EMT‑related biomarkers. The results of the present study indicated that the SUMOylation of HSP27 enhances the proliferation, invasion and migration of ESCC cells via PKM2.

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1	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
2	Liu Y, Liu J, Yin P, Liu S, Cai Y, You J, Zeng X, Wang L and Zhou M: The disease burden of malignant tumor in China, 1990 and 2010. Zhonghua Yu Fang Yi Xue Za Zhi. 49:309–314. 2015.(In Chinese). PubMed/NCBI
3	Zheng S, Vuitton L, Sheyhidin I, Vuitton DA, Zhang Y and Lu X: Northwestern China: A place to learn more on oesophageal cancer. Part one: Behavioural and environmental risk factors. Eur J Gastroenterol Hepatol. 22:917–925. 2010. View Article : Google Scholar : PubMed/NCBI
4	Lu XM, Monnier-Benoit S, Mo LZ, Xu SY, Prétet JL, Liu Z, Vuitton DA and Mougin C: Human papillomavirus in esophageal squamous cell carcinoma of the high-risk Kazakh ethnic group in Xinjiang, China. Eur J Surg Oncol. 34:765–770. 2008. View Article : Google Scholar : PubMed/NCBI
5	Liu F, Ma F, Wang Y, Hao L, Zeng H, Jia C, Wang Y, Liu P, Ong IM, Li B, et al: PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis. Nat Cell Biol. 19:1358–1370. 2017. View Article : Google Scholar : PubMed/NCBI
6	Wong N, Ojo D, Yan J and Tang D: PKM2 contributes to cancer metabolism. Cancer Lett. 356((2 Pt A)): 184–191. 2015. View Article : Google Scholar : PubMed/NCBI
7	Liu Z, Feng JG, Tuersun A, Liu T, Liu H, Liu Q, Zheng ST, Huang CG, Lv GD, Sheyhidin I and Lu XM: Proteomic identification of differentially-expressed proteins in esophageal cancer in three ethnic groups in Xinjiang. Mol Biol Rep. 38:3261–3269. 2011. View Article : Google Scholar : PubMed/NCBI
8	Liu Q, Liang M, Liu T, Vuitton L, Zheng S, Gao X, Lu M, Li X, Sheyhidin I and Lu X: M2 isoform of pyruvate kinase (PKM2) is upregulated in Kazakh's ESCC and promotes proliferation and migration of ESCC cells. Tumour Biol. 37:2665–2672. 2016. View Article : Google Scholar : PubMed/NCBI
9	Abdel-Haleem AM, Lewis NE, Jamshidi N, Mineta K, Gao X and Gojobori T: The emerging facets of non-cancerous warburg effect. Front Endocrinol (Lausanne). 8:2792017. View Article : Google Scholar : PubMed/NCBI
10	Wu J, Liu T, Rios Z, Mei Q, Lin X and Cao S: Heat shock proteins and cancer. Trends Pharmacol Sci. 38:226–256. 2017. View Article : Google Scholar : PubMed/NCBI
11	Saini J and Sharma PK: Clinical, prognostic and therapeutic significance of heat shock proteins in cancer. Curr Drug Targets. 19:1478–1490. 2018. View Article : Google Scholar : PubMed/NCBI
12	Zininga T, Ramatsui L and Shonhai A: Heat shock proteins as immunomodulants. Molecules. 23:28462018. View Article : Google Scholar
13	Han L, Jiang Y, Han D and Tan W: Hsp27 regulates epithelial mesenchymal transition, metastasis and proliferation in colorectal carcinoma. Oncol Lett. 16:5309–5316. 2018.PubMed/NCBI
14	Zhang Y, Feng Z, Wang W, Dong J, Gong X, Pu H and Chen X: Expression of heat shock protein-27 (Hsp27) and P38MAPK in esophageal squamous cell carcinoma. Med Sci Monit. 23:5246–5253. 2017. View Article : Google Scholar : PubMed/NCBI
15	Luz CC, Noguti J, Borges de Araujo L, Gianni MS, Simao Gomes T and Ricardo AN: Hsp27 and Hsp70 expression in esophageal squamous. Asian Pac J Cancer Prev. 18:789–794. 2017.PubMed/NCBI
16	Lee MS, Lee J, Lee S, Yoo SM, Kim JH, Kim WT, Kim WJ and Park J: Clinical, prognostic, and therapeutic significance of heat shock protein 27 in bladder cancer. Oncotarget. 9:7961–7974. 2018. View Article : Google Scholar : PubMed/NCBI
17	Liu J, Sha M, Wang Q, Ma Y, Geng X, Gao Y, Feng L and Shen Y and Shen Y: Small ubiquitin-related modifier 2/3 interacts with p65 and stabilizes it in the cytoplasm in HBV-associated hepatocellular carcinoma. BMC Cancer. 15:6752015. View Article : Google Scholar : PubMed/NCBI
18	Eifler K and Vertegaal ACO: SUMOylation-mediated regulation of cell cycle progression and cancer. Trends Biochem Sci. 40:779–793. 2015. View Article : Google Scholar : PubMed/NCBI
19	Princz A and Tavernarakis N: SUMOylation in Neurodegenerative Diseases. Gerontology. 66:122–130. 2020. View Article : Google Scholar : PubMed/NCBI
20	Dasso M: Biochemistry: Rear view of an enzyme. Nature. 497:576–577. 2013. View Article : Google Scholar : PubMed/NCBI
21	Ge H, Du J, Xu J, Meng X, Tian J, Yang J and Liang H: SUMOylation of HSP27 by small ubiquitin-like modifier 2/3 promotes proliferation and invasion of hepatocellular carcinoma cells. Cancer Biol Ther. 18:552–559. 2017. View Article : Google Scholar : PubMed/NCBI
22	Pellat A and Coriat R: Well differentiated grade 3 neuroendocrine tumors of the digestive tract: A narrative review. J Clin Med. 9:E16772020. View Article : Google Scholar : PubMed/NCBI
23	Zhang N, Ren Y, Wang Y, Zhao L, Wang B, Ma N, Gao Z and Cao B: LRG1 suppresses migration and invasion of esophageal squamous cell carcinoma by modulating epithelial to mesenchymal transition. J Cancer. 11:1486–1494. 2020. View Article : Google Scholar : PubMed/NCBI
24	Ma R, Liu Q, Zheng S, Liu T, Tan D and Lu X: PKM2-regulated STAT3 promotes esophageal squamous cell carcinoma progression via TGF-β1-induced EMT. J Cell Biochem. 12–Feb;2019.(Epub ahead of print). View Article : Google Scholar
25	Lang BJ, Guerrero-Gimenez ME, Prince TL, Ackerman A, Bonorino C and Calderwood SK: Heat shock proteins are essential components in transformation and tumor progression: Cancer cell intrinsic pathways and beyond. Int J Mol Sci. 20:45072019. View Article : Google Scholar
26	Marsden M, Nickells RW, Kapoor M and Browder LW: The induction of pyruvate kinase synthesis by heat shock in Xenopus laevis embryos. Dev Genet. 14:51–57. 1993. View Article : Google Scholar : PubMed/NCBI
27	Yang Z, Yang C, Xiao L, Liao X, Lan A, Wang X, Guo R, Chen P, Hu C and Feng J: Novel insights into the role of HSP90 in cytoprotection of H2S against chemical hypoxia-induced injury in H9c2 cardiac myocytes. Int J Mol Med. 28:397–403. 2011.PubMed/NCBI
28	Xu Q, Tu J, Dou C, Zhang J, Yang L, Liu X, Lei K, Liu Z, Wang Y, Li L, et al: HSP90 promotes cell glycolysis, proliferation and inhibits apoptosis by regulating PKM2 abundance via Thr-328 phosphorylation in hepatocellular carcinoma. Mol Cancer. 16:1782017. View Article : Google Scholar : PubMed/NCBI
29	Huang L, Yu Z, Zhang T, Zhao X and Huang G: HSP40 interacts with pyruvate kinase M2 and regulates glycolysis and cell proliferation in tumor cells. PLoS One. 9:e929492014. View Article : Google Scholar : PubMed/NCBI