Browse > Article
http://dx.doi.org/10.14348/molcells.2021.0012

Negative Regulation of Erythroid Differentiation via the CBX8-TRIM28 Axis  

Kim, Hyun Jeong (Department of Life Science, College of Natural Sciences, Chung-Ang University)
Park, Jin Woo (Department of Life Science, College of Natural Sciences, Chung-Ang University)
Kang, Joo-Young (Department of Life Science, College of Natural Sciences, Chung-Ang University)
Seo, Sang-Beom (Department of Life Science, College of Natural Sciences, Chung-Ang University)
Publication Information
Molecules and Cells / v.44, no.7, 2021 , pp. 444-457 More about this Journal
Abstract
Although the mechanism of chronic myeloid leukemia (CML) initiation through BCR/ABL oncogene has been well characterized, CML cell differentiation into erythroid lineage cells remains poorly understood. Using CRISPR-Cas9 screening, we identify Chromobox 8 (CBX8) as a negative regulator of K562 cell differentiation into erythrocytes. CBX8 is degraded via proteasomal pathway during K562 cell differentiation, which activates the expression of erythroid differentiation-related genes that are repressed by CBX8 in the complex of PRC1. During the differentiation process, the serine/threonine-protein kinase PIM1 phosphorylates serine 196 on CBX8, which contributes to CBX8 reduction. When CD235A expression levels are analyzed, the result reveals that the knockdown of PIM1 inhibits K562 cell differentiation. We also identify TRIM28 as another interaction partner of CBX8 by proteomic analysis. Intriguingly, TRIM28 maintains protein stability of CBX8 and TRIM28 loss significantly induces proteasomal degradation of CBX8, resulting in an acceleration of erythroid differentiation. Here, we demonstrate the involvement of the CBX8-TRIM28 axis during CML cell differentiation, suggesting that CBX8 and TRIM28 are promising novel targets for CML research.
Keywords
chromobox8; chronic myeloid leukemia; erythroid differentiation; serine/threonine-protein kinase pim-1; tripartite motif containing 28;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Shalem, O., Sanjana, N.E., Hartenian, E., Shi, X., Scott, D.A., Mikkelson, T., Heckl, D., Ebert, B.L., Root, D.E., Doench, J.G., et al. (2014). Genome-scale CRISPR-Cas9 knockout screening in human cells. Science 343, 84-87.   DOI
2 Park, S.J., Yoon, B.H., Kim, S.K., Kim, S.Y. (2019). GENT2: an updated gene expression database for normal and tumor tissues. BMC Med. Genomics 12, 101.   DOI
3 Pineda, C.T., Ramanathan, S., Fon Tacer, K., Weon, J.L., Potts, M.B., Ou, Y.H., White, M.A., Potts, P.R. (2015). Degradation of AMPK by a cancer-specific ubiquitin ligase. Cell 160, 715-728.   DOI
4 Dzierzak, E. and Philipsen, S. (2013). Erythropoiesis: development and differentiation. Cold Spring Harb. Perspect. Med. 3, a011601.
5 Beguin, Y. (1999). Erythropoietin and platelet production. Haematologica 84, 541-547.
6 Bhatlekar, S., Fields, J.Z., Boman, B.M. (2018). Role of HOX genes in stem cell differentiation and cancer. Stem Cells Int. 2018, 3569493.   DOI
7 Bixby, D. and Talpaz, M. (2009). Mechanisms of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and recent therapeutic strategies to overcome resistance. Hematology Am. Soc. Hematol. Educ. Program 2009, 461-476.   DOI
8 Koppens, M. and van Lohuizen, M. (2016). Context-dependent actions of Polycomb repressors in cancer. Oncogene 35, 1341-1352.   DOI
9 Jiang, X. and Chen, Z.J. (2011). The role of ubiquitylation in immune defence and pathogen evasion. Nat. Rev. Immunol. 12, 35-48.   DOI
10 Klauke, K., Radulovic, V., Broekhuis, M., Weersing, E., Zwart, E., Olthof, S., Ritsema, M., Bruggeman, S., Wu, X., Helin, K., et al. (2013). Polycomb Cbx family members mediate the balance between haematopoietic stem cell self-renewal and differentiation. Nat. Cell Biol. 15, 353-362.   DOI
11 Liu, Y., Shang, Y., Yan, Z., Li, H., Wang, Z., Liu, Z., Li, Z. (2019). Pim1 kinase positively regulates myoblast behaviors and skeletal muscle regeneration. Cell Death Dis. 10, 773.   DOI
12 Mikkers, H., Nawijn, M., Allen, J., Brouwers, C., Verhoeven, E., Jonkers, J., Berns, A. (2004). Mice deficient for all PIM kinases display reduced body size and impaired responses to hematopoietic growth factors. Mol. Cell. Biol. 24, 6104-6115.   DOI
13 Morey, L. and Helin, K. (2010). Polycomb group protein-mediated repression of transcription. Trends Biochem. Sci. 35, 323-332.   DOI
14 Deininger, M.W., Goldman, J.M., Melo, J.V. (2000). The molecular biology of chronic myeloid leukemia. Blood 96, 3343-3356.   DOI
15 Fong, K.W., Zhao, J.C., Song, B., Zheng, B., Yu, J. (2018). TRIM28 protects TRIM24 from SPOP-mediated degradation and promotes prostate cancer progression. Nat. Commun. 9, 5007.   DOI
16 Fursova, N.A., Blackledge, N.P., Nakayama, M., Ito, S., Koseki, Y., Farcas, A.M., King, H.W., Koseki, H., Klose, R.J. (2019). Synergy between variant PRC1 complexes defines polycomb-mediated gene repression. Mol. Cell 74, 1020-1036.e8.   DOI
17 Banerjee, S., Lu, J., Cai, Q., Sun, Z., Jha, H.C., Robertson, E.S. (2014). EBNA3C augments Pim-1 mediated phosphorylation and degradation of p21 to promote B-cell proliferation. PLoS Pathog. 10, e1004304.   DOI
18 Bodenmiller, B., Campbell, D., Gerrits, B., Lam, H., Jovanovic, M., Picotti, P., Schlapbach, R., Aebersold, R. (2008). PhosphoPep--a database of protein phosphorylation sites in model organisms. Nat. Biotechnol. 26, 1339-1340.   DOI
19 Bracken, A.P., Dietrich, N., Pasini, D., Hansen, K.H., Helin, K. (2006). Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 20, 1123-1136.   DOI
20 Bruserud, O., Gjertsen, B.T., Huang, T. (2000). Induction of differentiation and apoptosis- a possible strategy in the treatment of adult acute myelogenous leukemia. Oncologist 5, 454-462.   DOI
21 Di Carlo, V., Mocavini, I., Di Croce, L. (2019). Polycomb complexes in normal and malignant hematopoiesis. J. Cell Biol. 218, 55-69.   DOI
22 Doench, J.G., Fusi, N., Sullender, M., Hegde, M., Vaimberg, E.W., Donovan, K.F., Smith, I., Tothova, Z., Wilen, C., Orchard, R., et al. (2016). Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9. Nat. Biotechnol. 34, 184-191.   DOI
23 Doyle, J.M., Gao, J., Wang, J., Yang, M., Potts, PR. (2010). MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases. Mol. Cell 39, 963-974.   DOI
24 Daga, A., Podesta, M., Capra, M.C., Piaggio, G., Frassoni, F., Corte, G. (2000). The retroviral transduction of HOXC4 into human CD34(+) cells induces an in vitro expansion of clonogenic and early progenitors. Exp. Hematol. 28, 569-574.   DOI
25 Mouthon, M.A., Bernard, O., Mitjavila, M.T., Romeo, P.H., Vainchenker, W., Mathieu-Mahul, D. (1993). Expression of tal-1 and GATA-binding proteins during human hematopoiesis. Blood 81, 647-655.   DOI
26 Oza, J., Ganguly, B., Kulkarni, A., Ginjala, V., Yao, M., Ganesan, S. (2016). A novel role of chromodomain protein CBX8 in DNA damage response. J. Biol. Chem. 291, 22881-22893.   DOI
27 Park, J.W., Kang, J.Y., Hahm, J.Y., Kim, H.J., Seo, S.B. (2020). Proteosomal degradation of NSD2 by BRCA1 promotes leukemia cell differentiation. Commun. Biol. 3, 462.   DOI
28 Lee, S.S., Fu, N.Y., Sukumaran, S.K., Wan, K.F., Wan, Q., Yu, V.C. (2009). TRIM39 is a MOAP-1-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process. Exp. Cell Res. 315, 1313-1325.   DOI
29 Ma, Y.N., Chen, M.T., Wu, Z.K., Zhao, H.L., Yu, H.C., Yu, J., Zhang, J.W. (2013). Emodin can induce K562 cells to erythroid differentiation and improve the expression of globin genes. Mol. Cell. Biochem. 382, 127-136.   DOI
30 Kim, J.Y., Kee, H.J., Choe, N.W., Kim, S.M., Eom, G.H., Baek, H.J., Kook, H., Kook, H., Seo, S.B. (2008). Multiple-myeloma-related WHSC1/MMSET isoform RE-IIBP is a histone methyltransferase with transcriptional repression activity. Mol. Cell. Biol. 28, 2023-2034.   DOI
31 Saussele, S. and Silver, R.T. (2015). Management of chronic myeloid leukemia in blast crisis. Ann. Hematol. 94 Suppl 2, S159-S165.
32 Sawafuji, K., Miyakawa, Y., Kizaki, M., Ikeda, Y. (2003). Cyclosporin A induces erythroid differentiation of K562 cells through p38 MAPK and ERK pathways. Am. J. Hematol. 72, 67-69.   DOI
33 Senthilkumar, R. and Mishra, R.K. (2009). Novel motifs distinguish multiple homologues of Polycomb in vertebrates: expansion and diversification of the epigenetic toolkit. BMC Genomics 10, 549.   DOI
34 Sutherland, J.A., Turner, A.R., Mannoni, P., McGann, L.E., Turc, J.M. (1986). Differentiation of K562 leukemia cells along erythroid, macrophage, and megakaryocyte lineages. J. Biol. Response Mod. 5, 250-262.
35 Aplan, P.D., Nakahara, K., Orkin, S.H., Kirsch, I.R. (1992). The SCL gene product: a positive regulator of erythroid differentiation. EMBO J. 11, 4073-4081.   DOI
36 Hemenway, C.S., de Erkenez, A.C., Gould, G.C. (2001). The polycomb protein MPc3 interacts with AF9, an MLL fusion partner in t(9;11)(p22;q23) acute leukemias. Oncogene 20, 3798-3805.   DOI
37 Jagannathan-Bogdan, M. and Zon, L.I. (2013). Hematopoiesis. Development 140, 2463-2467.   DOI
38 Aloia, L., Di Stefano, B., Di Croce, L. (2013). Polycomb complexes in stem cells and embryonic development. Development 140, 2525-2534.   DOI
39 Bajaj, J., Hamilton, M., Shima, Y., Chambers, K., Spinler, K., Van Nostrand, E.L., Yee, B.A., Blue, S.M., Chen, M., Rizzeri, D., et al. (2020). An in vivo genome-wide CRISPR screen identifies the RNA-binding protein Staufen2 as a key regulator of myeloid leukemia. Nat. Cancer 1, 410-422.   DOI
40 Suzuki, M., Watanabe, M., Nakamaru, Y., Takagi, D., Takahashi, H., Fukuda, S., Hatakeyama, S. (2016). TRIM39 negatively regulates the NFkappaBmediated signaling pathway through stabilization of Cactin. Cell. Mol. Life Sci. 73, 1085-1101.   DOI
41 Tsiftsoglou, A.S., Vizirianakis, I.S., Strouboulis, J. (2009). Erythropoiesis: model systems, molecular regulators, and developmental programs. IUBMB Life 61, 800-830.   DOI
42 Vandamme, J., Volkel, P., Rosnoblet, C., Le Faou, P., Angrand, P.O. (2011). Interaction proteomics analysis of polycomb proteins defines distinct PRC1 complexes in mammalian cells. Mol. Cell. Proteomics 10, M110.002642.
43 Wang, H., Wang, L., Erdjument-Bromage, H., Vidal, M., Tempst, P., Jones, R.S., Zhang, Y. (2004). Role of histone H2A ubiquitination in Polycomb silencing. Nature 431, 873-878.   DOI
44 Wang, T., Wei, J.J., Sabatini, D.M., Lander, E.S. (2014). Genetic screens in human cells using the CRISPR-Cas9 system. Science 343, 80-84.   DOI
45 Wei, X., Yang, J., Adair, S.J., Ozturk, H., Kuscu, C., Lee, K.Y., Kane, W.J., O'Hara, P.E., Liu, D., Demirlenk, Y.M., et al. (2020). Targeted CRISPR screening identifies PRMT5 as synthetic lethality combinatorial target with gemcitabine in pancreatic cancer cells. Proc. Natl. Acad. Sci. U. S. A. 117, 28068-28079.   DOI
46 Weng, H., Huang, H., Wu, H., Qin, X., Zhao, B.S., Dong, L., Shi, H., Skibbe, J., Shen, C., Hu, C., et al. (2018). METTL14 inhibits hematopoietic stem/ progenitor differentiation and promotes leukemogenesis via mRNA m(6) A modification. Cell Stem Cell 22, 191-205.e9.   DOI
47 Whichard, Z.L., Sarkar, C.A., Kimmel, M., Corey, S.J. (2010). Hematopoiesis and its disorders: a systems biology approach. Blood 115, 2339-2347.   DOI
48 Zhan, X., Yang, J., Mao, Z., Yu, W. (2018). PIM1-catalyzed CBX8 phosphorylation promotes the oncogene-induced senescence of human diploid fibroblast. Biochem. Biophys. Res. Commun. 501, 779-785.   DOI
49 Park, J.W., Cho, H., Oh, H., Kim, J.Y., Seo, S.B. (2018). AURKA suppresses leukemic THP-1 cell differentiation through inhibition of the KDM6B pathway. Mol. Cells 41, 444-453.   DOI
50 Vu, L.P., Pickering, B.F., Cheng, Y., Zaccara, S., Nguyen, D., Minuesa, G., Chou, T., Chow, A., Saletore, Y., MacKay, M., et al. (2017). The N(6)-methyladenosine (m(6)A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat. Med. 23, 1369-1376.   DOI
51 Zhang, X. and Ren, R. (1998). Bcr-Abl efficiently induces a myeloproliferative disease and production of excess interleukin-3 and granulocyte-macrophage colony-stimulating factor in mice: a novel model for chronic myelogenous leukemia. Blood 92, 3829-3840.   DOI
52 Zhou, R.Q., Gong, Y.P., Guo, Y., Shan, Q.Q., Yang, X. (2012). [The effect of knockdown of transcription factor SCL/TAL-1 gene on the erythroid differentiation in EPO-induced K562 cell line]. Zhonghua Xue Ye Xue Za Zhi 33, 453-456. Chinese.
53 van Lohuizen, M., Verbeek, S., Krimpenfort, P., Domen, J., Saris, C., Radaszkiewicz, T., Berns, A. (1989). Predisposition to lymphomagenesis in pim-1 transgenic mice: cooperation with c-myc and N-myc in murine leukemia virus-induced tumors. Cell 56, 673-682.   DOI