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http://dx.doi.org/10.14348/molcells.2022.0014

Epigenetic Silencing of CHOP Expression by the Histone Methyltransferase EHMT1 Regulates Apoptosis in Colorectal Cancer Cells  

Kim, Kwangho (Korea Research Institute of Bioscience and Biotechnology)
Ryu, Tae Young (Korea Research Institute of Bioscience and Biotechnology)
Lee, Jinkwon (Korea Research Institute of Bioscience and Biotechnology)
Son, Mi-Young (Korea Research Institute of Bioscience and Biotechnology)
Kim, Dae-Soo (Korea Research Institute of Bioscience and Biotechnology)
Kim, Sang Kyum (College of Pharmacy, Chungnam National University)
Cho, Hyun-Soo (Korea Research Institute of Bioscience and Biotechnology)
Publication Information
Molecules and Cells / v.45, no.9, 2022 , pp. 622-630 More about this Journal
Abstract
Colorectal cancer (CRC) has a high mortality rate among cancers worldwide. To reduce this mortality rate, chemotherapy (5-fluorouracil, oxaliplatin, and irinotecan) or targeted therapy (bevacizumab, cetuximab, and panitumumab) has been used to treat CRC. However, due to various side effects and poor responses to CRC treatment, novel therapeutic targets for drug development are needed. In this study, we identified the overexpression of EHMT1 in CRC using RNA sequencing (RNA-seq) data derived from TCGA, and we observed that knocking down EHMT1 expression suppressed cell growth by inducing cell apoptosis in CRC cell lines. In Gene Ontology (GO) term analysis using RNA-seq data, apoptosis-related terms were enriched after EHMT1 knockdown. Moreover, we identified the CHOP gene as a direct target of EHMT1 using a ChIP (chromatin immunoprecipitation) assay with an anti-histone 3 lysine 9 dimethylation (H3K9me2) antibody. Finally, after cotransfection with siEHMT1 and siCHOP, we again confirmed that CHOP-mediated cell apoptosis was induced by EHMT1 knockdown. Our findings reveal that EHMT1 plays a key role in regulating CRC cell apoptosis, suggesting that EHMT1 may be a therapeutic target for the development of cancer inhibitors.
Keywords
apoptosis; C/EBP homologous protein; colorectal cancer; euchromatic histone-lysine N-methyltransferase 1;
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1 Jung, G., Hernandez-Illan, E., Moreira, L., Balaguer, F., and Goel, A. (2020). Epigenetics of colorectal cancer: biomarker and therapeutic potential. Nat. Rev. Gastroenterol. Hepatol. 17, 111-130.   DOI
2 Kim, K., Kwon, O., Ryu, T.Y., Jung, C.R., Kim, J., Min, J.K., Kim, D.S., Son, M.Y., and Cho, H.S. (2019). Propionate of a microbiota metabolite induces cell apoptosis and cell cycle arrest in lung cancer. Mol. Med. Rep. 20, 1569-1574.
3 Kim, S., Kim, J., Jung, Y., Jun, Y., Jung, Y., Lee, H.Y., Keum, J., Park, B.J., Lee, J., Kim, J., et al. (2020). Characterization of TNNC1 as a novel tumor suppressor of lung adenocarcinoma. Mol. Cells 43, 619-631.
4 Kleefstra, T., Kramer, J.M., Neveling, K., Willemsen, M.H., Koemans, T.S., Vissers, L.E., Wissink-Lindhout, W., Fenckova, M., van den Akker, W.M., Kasri, N.N., et al. (2012). Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Am. J. Hum. Genet. 91, 73-82.   DOI
5 Koopman, M., Antonini, N.F., Douma, J., Wals, J., Honkoop, A.H., Erdkamp, F.L., de Jong, R.S., Rodenburg, C.J., Vreugdenhil, G., Loosveld, O.J., et al. (2007). Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet 370, 135-142.   DOI
6 Kuipers, E.J., Grady, W.M., Lieberman, D., Seufferlein, T., Sung, J.J., Boelens, P.G., van de Velde, C.J., and Watanabe, T. (2015). Colorectal cancer. Nat. Rev. Dis. Primers 1, 15065.
7 Rozpedek, W., Pytel, D., Mucha, B., Leszczynska, H., Diehl, J.A., and Majsterek, I. (2016). The role of the PERK/eIF2α/ATF4/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress. Curr. Mol. Med. 16, 533-544.   DOI
8 Ohno, H., Shinoda, K., Ohyama, K., Sharp, L.Z., and Kajimura, S. (2013). EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex. Nature 504, 163-167.   DOI
9 Lin, S., Zhang, J., Chen, H., Chen, K., Lai, F., Luo, J., Wang, Z., Bu, H., Zhang, R., Li, H., et al. (2013). Involvement of endoplasmic reticulum stress in capsaicin-induced apoptosis of human pancreatic cancer cells. Evid. Based Complement. Alternat. Med. 2013, 629750.
10 Park, J.W., Woo, K.J., Lee, J.T., Lim, J.H., Lee, T.J., Kim, S.H., Choi, Y.H., and Kwon, T.K. (2007). Resveratrol induces pro-apoptotic endoplasmic reticulum stress in human colon cancer cells. Oncol. Rep. 18, 1269-1273.
11 Ryu, T.Y., Kim, K., Son, M.Y., Min, J.K., Kim, J., Han, T.S., Kim, D.S., and Cho, H.S. (2019). Downregulation of PRMT1, a histone arginine methyltransferase, by sodium propionate induces cell apoptosis in colon cancer. Oncol. Rep. 41, 1691-1699.
12 Olsen, J.B., Wong, L., Deimling, S., Miles, A., Guo, H., Li, Y., Zhang, Z., Greenblatt, J.F., Emili, A., and Tropepe, V. (2016). G9a and ZNF644 physically associate to suppress progenitor gene expression during neurogenesis. Stem Cell Reports 7, 454-470.   DOI
13 Park, S.K., Sanders, B.G., and Kline, K. (2010). Tocotrienols induce apoptosis in breast cancer cell lines via an endoplasmic reticulum stress-dependent increase in extrinsic death receptor signaling. Breast Cancer Res. Treat.124, 361-375.   DOI
14 Renneville, A., Van Galen, P., Canver, M.C., McConkey, M., Krill-Burger, J.M., Dorfman, D.M., Holson, E.B., Bernstein, B.E., Orkin, S.H., Bauer, D.E., et al. (2015). EHMT1 and EHMT2 inhibition induces fetal hemoglobin expression. Blood 126, 1930-1939.
15 Sanchez-Lopez, E., Zimmerman, T., Gomez del Pulgar, T., Moyer, M.P., Lacal Sanjuan, J.C., and Cebrian, A. (2013). Choline kinase inhibition induces exacerbated endoplasmic reticulum stress and triggers apoptosis via CHOP in cancer cells. Cell Death Dis. 4, e933.
16 Sung, H., Ferlay, J., Siegel, R.L., Laversanne, M., Soerjomataram, I., Jemal, A., and Bray, F. (2021). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209-249.   DOI
17 Carracedo, A., Gironella, M., Lorente, M., Garcia, S., Guzman, M., Velasco, G., and Iovanna, J.L. (2006). Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res.66, 6748-6755.   DOI
18 Guha, P., Kaptan, E., Gade, P., Kalvakolanu, D.V., and Ahmed, H. (2017). Tunicamycin induced endoplasmic reticulum stress promotes apoptosis of prostate cancer cells by activating mTORC1. Oncotarget 8, 68191-68207.   DOI
19 Chitnis, N.S., Pytel, D., Bobrovnikova-Marjon, E., Pant, D., Zheng, H., Maas, N.L., Frederick, B., Kushner, J.A., Chodosh, L.A., Koumenis, C., et al. (2012). miR-211 is a prosurvival microRNA that regulates chop expression in a PERK-dependent manner. Mol. Cell 48, 353-364.   DOI
20 Ea, C.K., Hao, S., Yeo, K.S., and Baltimore, D. (2012). EHMT1 protein binds to nuclear factor-κB p50 and represses gene expression. J. Biol. Chem. 287, 31207-31217.   DOI
21 Han, X., Luan, T., Sun, Y., Yan, W., Wang, D., and Zeng, X. (2020). MicroRNA 449c mediates the generation of monocytic myeloid-derived suppressor cells by targeting STAT6. Mol. Cells 43, 793-803.
22 Hsin, I.L., Hsiao, Y.C., Wu, M.F., Jan, M.S., Tang, S.C., Lin, Y.W., Hsu, C.P., and Ko, J.L. (2012). Lipocalin 2, a new GADD153 target gene, as an apoptosis inducer of endoplasmic reticulum stress in lung cancer cells. Toxicol. Appl. Pharmacol. 263, 330-337.   DOI
23 Thienpont, B., Aronsen, J.M., Robinson, E.L., Okkenhaug, H., Loche, E., Ferrini, A., Brien, P., Alkass, K., Tomasso, A., Agrawal, A., et al. (2017). The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy. J. Clin. Invest. 127, 335-348.
24 Wang, F., Fu, X.D., Zhou, Y., and Zhang, Y. (2009). Down-regulation of the cyclin E1 oncogene expression by microRNA-16-1 induces cell cycle arrest in human cancer cells. BMB Rep. 42, 725-730.   DOI
25 Wang, Y., Pei, X., Xu, P., Tan, Z., Zhu, Z., Zhang, G., Jiang, Z., and Deng, Z. (2020). E2F7, regulated by miR30c, inhibits apoptosis and promotes cell cycle of prostate cancer cells. Oncol. Rep. 44, 849-862.   DOI
26 Yang, Y., Shen, J., Yan, D., Yuan, B., Zhang, S., Wei, J., and Du, T. (2018). Euchromatic histone lysine methyltransferase 1 regulates cancer development in human gastric cancer by regulating E-cadherin. Oncol. Lett. 15, 9480-9486.
27 Ausserlechner, M.J., Obexer, P., Bock, G., Geley, S., and Kofler, R. (2004). Cyclin D3 and c-MYC control glucocorticoid-induced cell cycle arrest but not apoptosis in lymphoblastic leukemia cells. Cell Death Differ. 11, 165-174.   DOI
28 Baretti, M. and Azad, N.S. (2018). The role of epigenetic therapies in colorectal cancer. Curr. Probl. Cancer 42, 530-547.   DOI
29 Wang, Y., Zhu, L., Guo, M., Sun, G., Zhou, K., Pang, W., Cao, D., Tang, X., and Meng, X. (2021). Histone methyltransferase WHSC1 inhibits colorectal cancer cell apoptosis via targeting anti-apoptotic BCL2. Cell Death Discov. 7, 19.
30 Xie, Y.H., Chen, Y.X., and Fang, J.Y. (2020). Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct. Target. Ther. 5, 22.
31 Yuan, L., Zhang, Y., Xia, J., Liu, B., Zhang, Q., Liu, J., Luo, L., Peng, Z., Song, Z., and Zhu, R. (2015). Resveratrol induces cell cycle arrest via a p53- independent pathway in A549 cells. Mol. Med. Rep. 11, 2459-2464.   DOI
32 Zhang, M., Du, H., Huang, Z., Zhang, P., Yue, Y., Wang, W., Liu, W., Zeng, J., Ma, J., Chen, G., et al. (2018). Thymoquinone induces apoptosis in bladder cancer cell via endoplasmic reticulum stress-dependent mitochondrial pathway. Chem. Biol. Interact. 292, 65-75.   DOI
33 Hwang, S., Kim, S., Kim, K., Yeom, J., Park, S., and Kim, I. (2020). Euchromatin histone methyltransferase II (EHMT2) regulates the expression of ras-related GTP binding C (RRAGC) protein. BMB Rep. 53, 576-581.   DOI
34 Lee, J., Kim, K., Ryu, T.Y., Jung, C.R., Lee, M.S., Lim, J.H., Park, K., Kim, D.S., Son, M.Y., Hamamoto, R., et al. (2021). EHMT1 knockdown induces apoptosis and cell cycle arrest in lung cancer cells by increasing CDKN1A expression. Mol. Oncol. 15, 2989-3002.   DOI
35 Cebrian, A., Pharoah, P.D., Ahmed, S., Ropero, S., Fraga, M.F., Smith, P.L., Conroy, D., Luben, R., Perkins, B., Easton, D.F., et al. (2006). Genetic variants in epigenetic genes and breast cancer risk. Carcinogenesis 27, 1661-1669.   DOI
36 Guan, X., Zhong, X., Men, W., Gong, S., Zhang, L., and Han, Y. (2014). Analysis of EHMT1 expression and its correlations with clinical significance in esophageal squamous cell cancer. Mol. Clin. Oncol. 2, 76-80.   DOI
37 Herz, H.M., Garruss, A., and Shilatifard, A. (2013). SET for life: biochemical activities and biological functions of SET domain-containing proteins. Trends Biochem. Sci. 38, 621-639.   DOI
38 Huang, T., Lin, C., Zhong, L.L., Zhao, L., Zhang, G., Lu, A., Wu, J., and Bian, Z. (2017). Targeting histone methylation for colorectal cancer. Therap. Adv. Gastroenterol. 10, 114-131.   DOI