Login Register Cart 0
Generic placeholder image

Protein & Peptide Letters

Editor-in-Chief

ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

KIF20A Promotes CRC Progression and the Warburg Effect through the C-Myc/HIF-1α Axis

Author(s): Min Wu, Xianqiang Wu and Jie Han*

Volume 31, Issue 2, 2024

Published on: 30 November, 2023

Page: [107 - 115] Pages: 9

DOI: 10.2174/0109298665256238231120093150

Price: $65

Abstract

Background: Colorectal cancer (CRC) is a prevalent form of cancer globally, characterized by a high mortality rate. Therefore, discovering effective therapeutic approaches for CRC treatment is critical.

Methods: The levels of KIF20A in CRC clinical samples were determined using Western Blot and immunofluorescence assay. SW480 cells were transfected with siRNA targeting KIF20A, while HT-29 cells were transfected with a KIF20A overexpression vector. Cell viability and apoptosis of CRC cells were assessed using CCK-8 and TUNEL analysis. Migration ability was investigated using Transwell. The levels of pyruvate, lactate and ATP were determined through corresponding assay kits. Western Blot was applied to confirm the level of proteins associated with glycolysis, c- Myc, HIF-1α, PKM2 and LDHA. Subsequently, functional rescue experiments were conducted to investigate further the regulatory relationship between KIF20A, c-Myc, and HIF-1α in colorectal cancer (CRC), employing the c-Myc inhibitor 10058-F4 and c-Myc overexpression plasmids.

Results: KIF20A was up-regulated in vivo and in vitro in CRC. KIF20A knockdown inhibited cell viability and migration while promoting cell apoptosis in SW480 cells. Conversely, overexpression of KIF20A yielded contrasting effects in HT-29 cells. Moreover, inhibition of KIF20A restrained the pyruvate, lactate production and ATP level, whereas overexpression of KIF20A enhanced the Warburg effect. Western Blot indicated that knockdown KIF20A attenuated the levels of c-Myc, HIF-1α, PKM2 and LDHA. In addition, rescue experiments further verified that KIF20A enhanced the Warburg effect by the KIF20A/c-Myc/HIF-1α axis in CRC.

Conclusion: KIF20A, being a crucial regulator in the progression of CRC, has the potential to be a promising therapeutic target for the treatment of CRC.

Keywords: KIF20A, Warburg effect, c-Myc, HIF-1α, CRC, cell apoptosis.

Next »
Graphical Abstract

[1]
Aggarwal, A.; Prinz-Wohlgenannt, M.; Gröschel, C.; Tennakoon, S.; Meshcheryakova, A.; Chang, W.; Brown, E.M.; Mechtcheriakova, D.; Kállay, E. The calcium-sensing receptor suppresses epithelial-to-mesenchymal transition and stem cell- like phenotype in the colon. Mol. Cancer, 2015, 14(1), 61-61.
[http://dx.doi.org/10.1186/s12943-015-0330-4] [PMID: 25879211]
[2]
Tomasello, G.; Petrelli, F.; Ghidini, M.; Russo, A.; Passalacqua, R.; Barni, S. FOLFOXIRI plus bevacizumab as conversion therapy for patients with initially unresectable metastatic colorectal cancer. JAMA Oncol., 2017, 3(7), e170278-e170278.
[http://dx.doi.org/10.1001/jamaoncol.2017.0278] [PMID: 28542671]
[3]
Gaur, S.; Chen, L.; Ann, V.; Lin, W.C.; Wang, Y.; Chang, V.H.S.; Hsu, N.Y.; Shia, H.S.; Yen, Y. Dovitinib synergizes with oxaliplatin in suppressing cell proliferation and inducing apoptosis in colorectal cancer cells regardless of RAS-RAF mutation status. Mol. Cancer, 2014, 13(1), 21.
[http://dx.doi.org/10.1186/1476-4598-13-21] [PMID: 24495750]
[4]
Li, C.; Liu, X.; Liu, Y.; Liu, X.; Wang, R.; Liao, J.; Wu, S.; Fan, J.; Peng, Z.; Li, B.; Wang, Z. Keratin 80 promotes migration and invasion of colorectal carcinoma by interacting with PRKDC via activating the AKT pathway. Cell Death Dis., 2018, 9(10), 1009.
[http://dx.doi.org/10.1038/s41419-018-1030-y] [PMID: 30262880]
[5]
Alegria-Lertxundi, I.; Aguirre, C.; Bujanda, L.; Fernández, F.J.; Polo, F.; Ordovás, J.M.; Etxezarraga, M.C.; Zabalza, I.; Larzabal, M.; Portillo, I.; M de Pancorbo, M.; Palencia-Madrid, L.; Garcia-Etxebarria, K.; Rocandio, A.M.; Arroyo-Izaga, M. Gene-diet interactions in colorectal cancer: Survey design, instruments, participants and descriptive data of a case-control study in the basque country. Nutrients, 2020, 12(8), 2362.
[http://dx.doi.org/10.3390/nu12082362] [PMID: 32784647]
[6]
Tang, J.; Xu, J.; Zhi, Z.; Wang, X.; Wang, Y.; Zhou, Y.; Chen, R. MiR-876-3p targets KIF20A to block JAK2/STAT3 pathway in glioma. Am. J. Transl. Res., 2019, 11(8), 4957-4966.
[PMID: 31497212]
[7]
Chen, S.; Zhang, L.; Li, M.; Zhang, Y.; Sun, M.; Wang, L.; Lin, J.; Cui, Y.; Chen, Q.; Jin, C.; Li, X.; Wang, B.; Chen, H.; Zhou, T.; Wang, L.; Hsu, C.H.; Zhuo, W. Fusobacterium nucleatum reduces METTL3-mediated m6A modification and contributes to colorectal cancer metastasis. Nat. Commun., 2022, 13(1), 1248.
[http://dx.doi.org/10.1038/s41467-022-28913-5] [PMID: 35273176]
[8]
Zhou, Y.; Yang, L.; Xiong, L.; Wang, K.; Hou, X.; Li, Q.; Kong, F.; Liu, X.; He, J. KIF11 is upregulated in colorectal cancer and silencing of it impairs tumor growth and sensitizes colorectal cancer cells to oxaliplatin via p53/GSK3β signaling. J. Cancer, 2021, 12(12), 3741-3753.
[http://dx.doi.org/10.7150/jca.52103] [PMID: 33995648]
[9]
Nakamura, M.; Takano, A.; Thang, P.; Tsevegjav, B.; Zhu, M.; Yokose, T.; Yamashita, T.; Miyagi, Y.; Daigo, Y. Characterization of KIF20A as a prognostic biomarker and therapeutic target for different subtypes of breast cancer. Int. J. Oncol., 2020, 57(1), 277-288.
[http://dx.doi.org/10.3892/ijo.2020.5060] [PMID: 32467984]
[10]
Sheng, Y.; Wang, W.; Hong, B.; Jiang, X.; Sun, R.; Yan, Q.; Zhang, S.; Lu, M.; Wang, S.; Zhang, Z.; Lin, W.; Li, Y. Upregulation of KIF20A correlates with poor prognosis in gastric cancer. Cancer Manag. Res., 2018, 10, 6205-6216.
[http://dx.doi.org/10.2147/CMAR.S176147] [PMID: 30538567]
[11]
Saito, K.; Ohta, S.; Kawakami, Y.; Yoshida, K.; Toda, M. Functional analysis of KIF20A, a potential immunotherapeutic target for glioma. J. Neurooncol., 2017, 132(1), 63-74.
[http://dx.doi.org/10.1007/s11060-016-2360-1] [PMID: 28070829]
[12]
Wu, C.; Qi, X.; Qiu, Z.; Deng, G.; Zhong, L. Low expression of KIF20A suppresses cell proliferation, promotes chemosensitivity and is associated with better prognosis in HCC. Aging, 2021, 13(18), 22148-22163.
[http://dx.doi.org/10.18632/aging.203494] [PMID: 34491228]
[13]
Taniuchi, K.; Furihata, M.; Saibara, T. KIF20A-mediated RNA granule transport system promotes the invasiveness of pancreatic cancer cells. Neoplasia, 2014, 16(12), 1082-1093.
[http://dx.doi.org/10.1016/j.neo.2014.10.007] [PMID: 25499221]
[14]
Khongkow, P.; Gomes, A.R.; Gong, C.; Man, E.P.S.; Tsang, J.W-H.; Zhao, F.; Monteiro, L.J.; Coombes, R.C.; Medema, R.H.; Khoo, U.S.; Lam, E.W-F. Paclitaxel targets FOXM1 to regulate KIF20A in mitotic catastrophe and breast cancer paclitaxel resistance. Oncogene, 2016, 35(8), 990-1002.
[http://dx.doi.org/10.1038/onc.2015.152] [PMID: 25961928]
[15]
Chen, D.; Wang, Y.; Lu, R.; Jiang, X.; Chen, X.; Meng, N.; Chen, M.; Xie, S.; Yan, G.R. E3 ligase ZFP91 inhibits hepatocellular carcinoma metabolism reprogramming by regulating PKM splicing. Theranostics, 2020, 10(19), 8558-8572.
[http://dx.doi.org/10.7150/thno.44873] [PMID: 32754263]
[16]
Flaveny, C.A.; Griffett, K.; El-Gendy, B.E.D.M.; Kazantzis, M.; Sengupta, M.; Amelio, A.L.; Chatterjee, A.; Walker, J.; Solt, L.A.; Kamenecka, T.M.; Burris, T.P. Broad anti-tumor activity of a small molecule that selectively targets the warburg effect and lipogenesis. Cancer Cell, 2015, 28(1), 42-56.
[http://dx.doi.org/10.1016/j.ccell.2015.05.007] [PMID: 26120082]
[17]
Hao, S.; Luo, C.; Abukiwan, A.; Wang, G.; He, J.; Huang, L.; Weber, C.E.M.; Lv, N.; Xiao, X.; Eichmüller, S.B.; He, D. miR-137 inhibits proliferation of melanoma cells by targeting PAK 2. Exp. Dermatol., 2015, 24(12), 947-952.
[http://dx.doi.org/10.1111/exd.12812] [PMID: 26186482]
[18]
Yin, X.; Zhang, B.H.; Zheng, S.S.; Gao, D.M.; Qiu, S.J.; Wu, W.Z.; Ren, Z.G. Coexpression of gene Oct4 and Nanog initiates stem cell characteristics in hepatocellular carcinoma and promotes epithelial-mesenchymal transition through activation of Stat3/Snail signaling. J. Hematol. Oncol., 2015, 8(1), 23.
[http://dx.doi.org/10.1186/s13045-015-0119-3] [PMID: 25879771]
[19]
Lai, Y.; Lin, P.; Chen, M.; Zhang, Y.; Chen, J.; Zheng, M.; Liu, J.; Du, H.; Chen, R.; Pan, X.; Liu, N.; Chen, H. Restoration of L-OPA1 alleviates acute ischemic stroke injury in rats via inhibiting neuronal apoptosis and preserving mitochondrial function. Redox Biol., 2020, 34, 101503.
[http://dx.doi.org/10.1016/j.redox.2020.101503] [PMID: 32199783]
[20]
Ma, H.; Wang, X.; Zhang, W.; Li, H.; Zhao, W.; Sun, J.; Yang, M. Melatonin suppresses ferroptosis induced by high glucose via activation of the Nrf2/HO-1 signaling pathway in type 2 diabetic osteoporosis. Oxid. Med. Cell. Longev., 2020, 2020, 1-18.
[http://dx.doi.org/10.1155/2020/9067610] [PMID: 33343809]
[21]
Zhang, H.; Pan, K.; Wang, H.; Weng, D.; Song, H.; Zhou, J.; Huang, W.; Li, J.; Chen, M.; Xia, J. Decreased expression of ING2 gene and its clinicopathological significance in hepatocellular carcinoma. Cancer Lett., 2008, 261(2), 183-192.
[http://dx.doi.org/10.1016/j.canlet.2007.11.019] [PMID: 18160212]
[22]
Jin, H.F.; Wang, J.F.; Shao, M.; Zhou, K.; Ma, X.; Lv, X.P. Down-regulation of miR-7 in gastric cancer is associated with elevated LDH-A expression and chemoresistance to cisplatin. Front. Cell Dev. Biol., 2020, 8, 555937.
[http://dx.doi.org/10.3389/fcell.2020.555937] [PMID: 33072745]
[23]
Zhang, R.; Shen, W.; Du, J.; Gillies, M.C. Selective knockdown of hexokinase 2 in rods leads to age-related photoreceptor degeneration and retinal metabolic remodeling. Cell Death Dis., 2020, 11(10), 885.
[http://dx.doi.org/10.1038/s41419-020-03103-7] [PMID: 33082308]
[24]
Shen, T.; Yang, L.; Zhang, Z.; Yu, J.; Dai, L.; Gao, M.; Shang, Z.; Niu, Y. KIF20A affects the prognosis of bladder cancer by promoting the proliferation and metastasis of bladder cancer cells. Dis. Markers, 2019, 2019, 1-9.
[http://dx.doi.org/10.1155/2019/4863182] [PMID: 31093305]
[25]
Ren, X.; Chen, X.; Ji, Y.; Li, L.; Li, Y.; Qin, C.; Fang, K. Upregulation of KIF20A promotes tumor proliferation and invasion in renal clear cell carcinoma and is associated with adverse clinical outcome. Aging, 2020, 12(24), 25878-25894.
[http://dx.doi.org/10.18632/aging.202153] [PMID: 33232285]
[26]
Li, T.F.; Zeng, H.J.; Shan, Z.; Ye, R.Y.; Cheang, T.Y.; Zhang, Y.J.; Lu, S.H.; Zhang, Q.; Shao, N.; Lin, Y. Overexpression of kinesin superfamily members as prognostic biomarkers of breast cancer. Cancer Cell Int., 2020, 20(1), 123.
[http://dx.doi.org/10.1186/s12935-020-01191-1] [PMID: 32322170]
[27]
Chu, Y.; Chen, Y.; Li, M.; Shi, D.; Wang, B.; Lian, Y.; Cheng, X.; Wang, X.; Xu, M.; Cheng, T.; Shi, J.; Yuan, W. Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia. Cancer Sci., 2019, 110(7), 2200-2210.
[http://dx.doi.org/10.1111/cas.14033] [PMID: 31050834]
[28]
Peng, W.; Huang, W.; Ge, X.; Xue, L.; Zhao, W.; Xue, J. Type Iγ phosphatidylinositol phosphate kinase promotes tumor growth by facilitating Warburg effect in colorectal cancer. EBioMedicine, 2019, 44, 375-386.
[http://dx.doi.org/10.1016/j.ebiom.2019.05.015] [PMID: 31105034]
[29]
Osthus, R.C.; Shim, H.; Kim, S.; Li, Q.; Reddy, R.; Mukherjee, M.; Xu, Y.; Wonsey, D.; Lee, L.A.; Dang, C.V. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J. Biol. Chem., 2000, 275(29), 21797-21800.
[http://dx.doi.org/10.1074/jbc.C000023200] [PMID: 10823814]
[30]
Li, Y.; Sun, X.X.; Qian, D.Z.; Dai, M.S. Molecular crosstalk between MYC and HIF in cancer. Front. Cell Dev. Biol., 2020, 8, 590576.
[http://dx.doi.org/10.3389/fcell.2020.590576] [PMID: 33251216]
[31]
Moldogazieva, N.T.; Mokhosoev, I.M.; Terentiev, A.A. Metabolic heterogeneity of cancer cells: An interplay between HIF-1, GLUTs, and AMPK. Cancers, 2020, 12(4), 862.
[http://dx.doi.org/10.3390/cancers12040862] [PMID: 32252351]
[32]
Weng, M.; Chen, W.; Chen, X.; Lu, H.; Sun, Z.; Yu, Q.; Sun, P.; Xu, Y.; Zhu, M.; Jiang, N.; Zhang, J.; Zhang, J.; Song, Y.; Ma, D.; Zhang, X.; Miao, C. Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression. Nat. Commun., 2020, 11(1), 1869.
[http://dx.doi.org/10.1038/s41467-020-15795-8] [PMID: 32313017]
[33]
Fang, Y.; Shen, Z.Y.; Zhan, Y.Z.; Feng, X.C.; Chen, K.L.; Li, Y.S.; Deng, H.J.; Pan, S.M.; Wu, D.H.; Ding, Y. CD36 inhibits β-catenin/c-myc-mediated glycolysis through ubiquitination of GPC4 to repress colorectal tumorigenesis. Nat. Commun., 2019, 10(1), 3981.
[http://dx.doi.org/10.1038/s41467-019-11662-3] [PMID: 31484922]

Rights & Permissions Print Cite
Article Metrics
16
1
© 2024 Bentham Science Publishers | Privacy Policy