Background/Aims: Adhesion-regulating molecule 1 (ADRM1), a receptor located on the 26S proteasome, is upregulated in many solid cancers. However, little is known about its role in acute leukemia (AL). Methods: We determined ADRM1 expression levels in both untreated AL samples and leukemia cell lines using real-time polymerase chain reaction or Western blot analysis. Growth curves, colony formation assays, cell cycle and apoptosis analyses, cell migration and invasion assays and NF-κB p65 nuclear translocation assays via Western blotting were used to examine the biological behavior of HL60 cells and the underlying mechanism. Results: ADRM1 was upregulated in both untreated AL samples and leukemia cell lines. ADRM1 knockdown significantly suppressed HL60 cell proliferation (48.82 ± 12.58%) and colony formation and caused cell cycle arrest in the G0/G1 phase. Furthermore, we confirmed that ADRM1 knockdown suppressed p65 nuclear translocation. Conclusion: Our study revealed that ADRM1 was overexpressed in AL, especially in CD34+ leukemia stem and progenitor cells. ADRM1 may play a role in AL via the proteasome-ubiquitin pathway by potentially sustaining the activation of NF-κB signaling.

Keywords:
Adhesion-regulating molecule 1, Acute leukemia, Suppressed HL60 cell proliferation
1.
Jørgensen JP, Lauridsen AM, Kristensen P, Dissing K, Johnsen AH, Hendil KB, Hartmann-Petersen R: Adrm1, a putative cell adhesion regulating protein, is a novel proteasome-associated factor. J Mol Biol 2006;360:1043-1052.
2.
Qiu XB, Ouyang SY, Li CJ, Miao S, Wang L, Goldberg AL: hRpn13/ADRM1/GP110 is a novel proteasome subunit that binds the deubiquitinating enzyme, UCH37. EMBO J 2006;25:5742-5753.
3.
Husnjak K, Elsasser S, Zhang N, Chen X, Randles L, Shi Y, Hofmann K, Walters KJ, Finley D, Dikic I: Proteasome subunit Rpn13 is a novel ubiquitin receptor. Nature 2008;453:481-488.
4.
Schreiner P, Chen X, Husnjak K, Randles L, Zhang N, Elsasser S, Finley D, Dikic I, Walters KJ, Groll M: Ubiquitin docking at the proteasome through a novel pleckstrin-homology domain interaction. Nature 2008;453:548-552.
5.
Besche HC, Sha Z, Kukushkin NV, Peth A, Hock EM, Kim W, Gygi S, Gutierrez JA, Liao H, Dick L, Goldberg AL: Autoubiquitination of the 26S proteasome on Rpn13 regulates breakdown of ubiquitin conjugates. EMBO J 2014;33:1159-1176.
6.
Chen X, Lee BH, Finley D, Walters KJ: Structure of proteasome ubiquitin receptor hRpn13 and its activation by the scaffolding protein hRpn2. Mol Cell 2010;38:404-415.
7.
Hamazaki J, Iemura S, Natsume T, Yashiroda H, Tanaka K, Murata S: A novel proteasome interacting protein recruits the deubiquitinating enzyme UCH37 to 26S proteasomes. EMBO J 2006;25:4524-4536.
8.
Yao T, Song L, Xu W, DeMartino GN, Florens L, Swanson SK, Washburn MP, Conaway RC, Conaway JW, Cohen RE: Proteasome recruitment and activation of the Uch37 deubiquitinating enzyme by Adrm1. Nat Cell Biol 2006;8:994-1002.
9.
Jiao L, Ouyang S, Shaw N, Song G, Feng Y, Niu F, Qiu W, Zhu H, Hung LW, Zuo X, Eleonora Shtykova V, Zhu P, Dong YH, Xu R, Liu ZJ: Mechanism of the Rpn13-induced activation of Uch37. Protein Cell 2014;5:616-630.
10.
Mazumdar T, Gorgun FM, Sha Y, Tyryshkin A, Zeng S, Hartmann-Petersen R, Jørgensen JP, Hendil KB, Eissa NT: Regulation of NF-kappaB activity and inducible nitric oxide synthase by regulatory particle non-ATPase subunit 13 (Rpn13). Proc Natl Acad Sci U S A 2010;107:13854-13859.
11.
Yang X, Miao X, Wen Y, Hu J, Dai W, Yin B: A possible connection between adhesion regulating molecule 1 overexpression and nuclear factor kappa B activity in hepatocarcinogenesis. Oncol Rep 2012;28:283-290.
12.
Fejzo MS, Dering J, Ginther C, Anderson L, Ramos L, Walsh C, Karlan B, Slamon DJ: Comprehensive analysis of 20q13 genes in ovarian cancer identifies ADRM1 as amplification target. Genes Chromosomes Cancer 2008;47:873-883.
13.
Tabach Y, Kogan-Sakin I, Buganim Y, Solomon H, Goldfinger N, Hovland R, Ke XS, Oyan AM, Kalland KH, Rotter V, Domany E: Amplification of the 20q chromosomal arm occurs early in tumorigenic transformation and may initiate cancer. PLoS One 2011;6:e14632.
14.
Simins AB, Weighardt H, Weidner KM, Weidle UH, Holzmann B: Functional cloning of ARM-1, an adhesion-regulating molecule up-regulated in metastatic tumor cells. Clin Exp Metastasis 1999;17:641-648.
15.
Pilarsky C, Wenzig M, Specht T, Saeger HD, Grützmann R: Identification and validation of commonly overexpressed genes in solid tumors by comparison of microarray data. Neoplasia 2004;6:744-750.
16.
Sillars-Hardebol AH, Carvalho B, de Wit M, Postma C, Delis-van Diemen PM, Mongera S, Ylstra B, van de Wiel MA, Meijer GA, Fijneman RJ: Identification of key genes for carcinogenic pathways associated with colorectal adenoma-to-carcinoma progression. Tumour Biol 2010;31:89-96.
17.
Jang SH, Park JW, Kim HR, Seong JK, Kim HK: ADRM1 gene amplification is a candidate driver for metastatic gastric cancers. Clin Exp Metastasis 2014;31:727-733.
18.
Chen W, Hu XT, Shi QL, Zhang FB, He C: Knockdown of the novel proteasome subunit Adrm1 located on the 20q13 amplicon inhibits colorectal cancer cell migration, survival and tumorigenicity. Oncol Rep 2009;21:531-537.
19.
Fejzo MS, Anderson L, von Euw EM, Kalous O, Avliyakulov NK, Haykinson MJ, Konecny GE, Finn RS, Slamon DJ: Amplification target ADRM1: role as an oncogene and therapeutic target for ovarian cancer. Int J Mol Sci 2013;14:3094-3109.
20.
Ravid T, Hochstrasser M: Diversity of degradation signals in the ubiquitin-proteasome system. Nat Rev Mol Cell Biol 2008;9:679-690.
21.
Schwartz AL, Ciechanover A: Targeting proteins for destruction by the ubiquitin system: implications for human pathobiology. Annu Rev Pharmacol Toxicol 2009;49:73-96.
22.
Anchoori RK, Karanam B, Peng S, Wang JW, Jiang R, Tanno T, Orlowski RZ, Matsui W, Zhao M, Rudek MA, Hung CF, Chen X, Walters KJ, Roden RB: A bis-benzylidine piperidone targeting proteasome ubiquitin receptor RPN13/ADRM1 as a therapy for cancer. Cancer Cell 2013;24:791-805.
23.
Pacifico F, Leonardi A: NF-kappaB in solid tumors. Biochem Pharmacol 2006;72:1142-1152.
24.
Hinz M, Krappmann D, Eichten A, Heder A, Scheidereit C, Strauss M: NF-kappaB function in growth control: regulation of cyclin D1 expression and G0/G1-to-S-phase transition. Mol Cell Biol 1999;19:2690-2698.
25.
Hsia CY, Cheng S, Owyang AM, Dowdy SF, Liou HC: c-Rel regulation of the cell cycle in primary mouse B lymphocytes. Int Immunol 2002;14:905-916.
26.
Kim DW, Gazourian L, Quadri SA, Romieu-Mourez R, Sherr DH, Sonenshein GE: The RelA NF-kappaB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells. Oncogene 2000;19:5498-5506.
27.
Hinz M, Löser P, Mathas S, Krappmann D, Dörken B, Scheidereit C: Constitutive NF-kappaB maintains high expression of a characteristic gene network, including CD40, CD86, and a set of antiapoptotic genes in Hodgkin/Reed-Sternberg cells. Blood 2001;97:2798-2807.
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2015
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