Abstract
MYB Proto-Oncogene Like 2 (MYBL2) is a highly conserved member of the Myb family of transcription factors and plays a critical role in regulating cell proliferation and survival. Here we show that overexpression of MYBL2 is frequently observed in lung adenocarcinoma (LUAD) and significantly correlates with advanced stage and poor patient survival. Knockdown of MYBL2 induced apoptosis in lung cancer cells and resulted in significant inhibition of cell proliferation, migration, and invasion. Notably, we identified Non-SMC Condensin I Complex Subunit H (NCAPH) gene as a direct target of MYBL2. NCAPH expression is highly correlated with that of MYBL2 in LUAD cases and is tightly affected by MYBL2 knockdown or overexpression in vitro. Chromatin immunoprecipitation (ChIP) assays also showed that MYBL2 directly binds to the transcription start site (TSS) of NCAPH. Moreover, we provided evidence that NCAPH functions as an oncogene in lung cancer and overexpression of NCAPH could partially rescue cell death and migration blockage induced by MYBL2 knockdown. Together, these results suggest that overexpression of MYBL2 promotes proliferation and migration of lung cancer cells via upregulating NCAPH, establishing their roles as novel prognostic biomarkers as well as potential therapeutic targets for the disease.
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References
Sandberg ML, Sutton SE, Pletcher MT, Wiltshire T, Tarantino LM, Hogenesch JB, Cooke MP (2005) c-Myb and p300 regulate hematopoietic stem cell proliferation and differentiation. Dev Cell 8:153–166. https://doi.org/10.1016/j.devcel.2004.12.015
Frau M, Ladu S, Calvisi DF, Simile MM, Bonelli P, Daino L, Tomasi ML, Seddaiu MA, Feo F, Pascale RM (2011) Mybl2 expression is under genetic control and contributes to determine a hepatocellular carcinoma susceptible phenotype. J Hepatol 55:111–119. https://doi.org/10.1016/j.jhep.2010.10.031
Ren F, Wang L, Shen X, Xiao X, Liu Z, Wei P, Wang Y, Qi P, Shen C, Sheng W, Du X (2015) MYBL2 is an independent prognostic marker that has tumor-promoting functions in colorectal cancer. Am J Cancer Res 5:1542–1552
Sala A (2012) c-MYB and TGFbeta: EMT's dynamic duo in breast cancer. Cell Cycle 11:17. https://doi.org/10.4161/cc.11.1.18733
Chen J, Chen X (2018) MYBL2 is targeted by miR-143-3p and regulates breast cancer cell proliferation and apoptosis. Oncol Res 26:913–922. https://doi.org/10.3727/096504017X15135941182107
Yuan J, Zhang Y, Sheng Y, Fu X, Cheng H, Zhou R (2015) MYBL2 guides autophagy suppressor VDAC2 in the developing ovary to inhibit autophagy through a complex of VDAC2-BECN1-BCL2L1 in mammals. Autophagy 11:1081–1098. https://doi.org/10.1080/15548627.2015.1040970
Martin CM, Astbury K, Kehoe L, O'Crowley JB, O'Toole S, O'Leary JJ (2015) The use of MYBL2 as a novel candidate biomarker of cervical cancer. Methods Mol Biol 1249:241–251. https://doi.org/10.1007/978-1-4939-2013-6_18
Heinrichs S, Conover LF, Bueso-Ramos CE, Kilpivaara O, Stevenson K, Neuberg D, Loh ML, Wu WS, Rodig SJ, Garcia-Manero G, Kantarjian HM, Look AT (2013) MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy. Elife 2:e00825. https://doi.org/10.7554/eLife.00825
Tanaka Y, Patestos NP, Maekawa T, Ishii S (1999) B-myb is required for inner cell mass formation at an early stage of development. J Biol Chem 274:28067–28070. https://doi.org/10.1074/jbc.274.40.28067
Lorvellec M, Dumon S, Maya-Mendoza A, Jackson D, Frampton J, Garcia P (2010) B-Myb is critical for proper DNA duplication during an unperturbed S phase in mouse embryonic stem cells. Stem Cells 28:1751–1759. https://doi.org/10.1002/stem.496
Ward C, Volpe G, Cauchy P, Ptasinska A, Almaghrabi R, Blakemore D, Nafria M, Kestner D, Frampton J, Murphy G, Buganim Y, Kaji K, Garcia P (2018) Fine-tuning Mybl2 is required for proper mesenchymal-to-epithelial transition during somatic reprogramming. Cell Rep 24(1496–1511):e8. https://doi.org/10.1016/j.celrep.2018.07.026
Shi H, Bevier M, Johansson R, Enquist-Olsson K, Henriksson R, Hemminki K, Lenner P, Forsti A (2012) Prognostic impact of polymorphisms in the MYBL2 interacting genes in breast cancer. Breast Cancer Res Treat 131:1039–1047. https://doi.org/10.1007/s10549-011-1826-2
Clarke M, Dumon S, Ward C, Jager R, Freeman S, Dawood B, Sheriff L, Lorvellec M, Kralovics R, Frampton J, Garcia P (2013) MYBL2 haploinsufficiency increases susceptibility to age-related haematopoietic neoplasia. Leukemia 27:661–670. https://doi.org/10.1038/leu.2012.241
Fujii K, Murase T, Beppu S, Saida K, Takino H, Masaki A, Ijichi K, Kusafuka K, Iida Y, Onitsuka T, Yatabe Y, Hanai N, Hasegawa Y, Inagaki H (2017) MYB, MYBL1, MYBL2 and NFIB gene alterations and MYC overexpression in salivary gland adenoid cystic carcinoma. Histopathology 71:823–834. https://doi.org/10.1111/his.13281
Liang HB, Cao Y, Ma Q, Shu YJ, Wang Z, Zhang F, Ye YY, Li HF, Xiang SS, Song XL, Xu Y, Zhang YC, Bao RF, Yuan RY, Zhang YJ, Hu YP, Jiang L, Li ML, Wang XA, Wu XS, Wu WG, Zhao S, Fand Y, Cui XP, Lu YS, Zhou J, Zheng L, Gong W, Liu YB (2017) MYBL2 is a potential prognostic marker that promotes cell proliferation in gallbladder cancer. Cell Physiol Biochem 41:2117–2131. https://doi.org/10.1159/000475454
Musa J, Aynaud MM, Mirabeau O, Delattre O, Grunewald TG (2017) MYBL2 (B-Myb): a central regulator of cell proliferation, cell survival and differentiation involved in tumorigenesis. Cell Death Dis 8:e2895. https://doi.org/10.1038/cddis.2017.244
Shao M, Ren Z, Zhang R (2018) MYBL2 protects against H9c2 injury induced by hypoxia via AKT and NFkappaB pathways. Mol Med Rep 17:4832–4838. https://doi.org/10.3892/mmr.2018.8387
Jia Y, Gao Y, Li J, Chang Z, Yan J, Qin Y (2019) Prognostic implications of MYBL2 in resected Chinese gastric adenocarcinoma patients. Onco Targets Ther 12:1129–1135. https://doi.org/10.2147/OTT.S188820
Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z (2017) GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 45:W98–W102. https://doi.org/10.1093/nar/gkx247
Yin L, Jiang LP, Shen QS, Xiong QX, Zhuo X, Zhang LL, Yu HJ, Guo X, Luo Y, Dong J, Kong QP, Yang CP, Chen YB (2017) NCAPH plays important roles in human colon cancer. Cell Death Dis 8:e2680. https://doi.org/10.1038/cddis.2017.88
Shimomura H, Sasahira T, Nakashima C, Kurihara-Shimomura M, Kirita T (2019) Non-SMC condensin I complex subunit H (NCAPH) is associated with lymphangiogenesis and drug resistance in oral squamous cell carcinoma. J Clin Med. https://doi.org/10.3390/jcm9010072
Cui F, Hu J, Xu Z, Tan J, Tang H (2019) Overexpression of NCAPH is upregulated and predicts a poor prognosis in prostate cancer. Oncol Lett 17:5768–5776. https://doi.org/10.3892/ol.2019.10260
Arai T, Kojima S, Yamada Y, Sugawara S, Kato M, Yamazaki K, Naya Y, Ichikawa T, Seki N (2019) Micro-ribonucleic acid expression signature of metastatic castration-resistant prostate cancer: regulation of NCAPH by antitumor miR-199a/b-3p. Int J Urol 26:506–520. https://doi.org/10.1111/iju.13911
Ahmed F (2019) Integrated network analysis reveals FOXM1 and MYBL2 as key regulators of cell proliferation in non-small cell lung cancer. Front Oncol 9:1011. https://doi.org/10.3389/fonc.2019.01011
Guan Z, Cheng W, Huang D, Wei A (2018) High MYBL2 expression and transcription regulatory activity is associated with poor overall survival in patients with hepatocellular carcinoma. Curr Res Transl Med 66:27–32. https://doi.org/10.1016/j.retram.2017.11.002
Fan X, Wang Y, Jiang T, Cai W, Jin Y, Niu Y, Zhu H, Bu Y (2018) B-Myb mediates proliferation and migration of non-small-cell lung cancer via suppressing IGFBP3. Int J Mol Sci. https://doi.org/10.3390/ijms19051479
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This work was supported by Scientific Research Foundation of the Education Department of Jiangxi Province (Grant Numbers: GJJ14003) and Natural Science Foundation of Jiangxi Province (Grant Numbers: 20143ACB20011)
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Xiong, YC., Wang, J., Cheng, Y. et al. Overexpression of MYBL2 promotes proliferation and migration of non-small-cell lung cancer via upregulating NCAPH. Mol Cell Biochem 468, 185–193 (2020). https://doi.org/10.1007/s11010-020-03721-x
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DOI: https://doi.org/10.1007/s11010-020-03721-x