Addiction of MYCN Amplified Tumours to B-MYB Underscores a Reciprocal Regulatory Loop

Overview

Journal Oncotarget

Specialty Oncology

Date 2011 Feb 10

PMID 21304178

Citations 27

Authors

Francesco Gualdrini

Daisy Corvetta

Sandra Cantilena

Olesya Chayka

Barbara Tanno

Giuseppe Raschella

Arturo Sala

Affiliations

Soon will be listed here.

Abstract

MYCN is a member of the MYC family of oncoproteins frequently amplified or overexpressed in aggressive, paediatric tumours of the nervous system. In this study we have identified the gene B-MYB, encoding the transcription factor also known as MYBL2, as a downstream target of MYCN. Using multiple in silico databases we show that expression of B-MYB significantly correlates with that of MYCN in neuroblastoma patients. MYCN binds to and activates the B-MYB gene in vivo and in vitro. Blunting B-MYB expression by RNA interference causes reduced proliferation of MYCN amplified, but not MYCN-non amplified, neuroblastoma cell lines, indicating that tumour cells are addicted to B-MYB in a MYCN dependent manner. Notably, B-MYB binds in vivo to the MYCN amplicon and is required for its expression. We conclude that MYCN and B-MYB are engaged in a reciprocal regulatory loop whose pharmacological targeting could be beneficial to patients with the aggressive forms of cancer in which MYCN is amplified.

Citing Articles

Extrachromosomal circular DNA and their roles in cancer progression.

Zheng S, Li Y, Wang L, Wei Q, Wei M, Yu T Genes Dis. 2024; 12(1):101202.

PMID: 39534571 PMC: 11554924. DOI: 10.1016/j.gendis.2023.101202.

MYB oncoproteins: emerging players and potential therapeutic targets in human cancer.

Ciciro Y, Sala A Oncogenesis. 2021; 10(2):19.

PMID: 33637673 PMC: 7910556. DOI: 10.1038/s41389-021-00309-y.

Association between B- proto-oncogene and the development of malignant tumors.

Jin Y, Qi G, Chen G, Wang C, Fan X Oncol Lett. 2021; 21(2):166.

PMID: 33552284 PMC: 7798104. DOI: 10.3892/ol.2021.12427.

Prognostic implications of MYBL2 in resected Chinese gastric adenocarcinoma patients.

Jia Y, Gao Y, Li J, Chang Z, Yan J, Qin Y Onco Targets Ther. 2019; 12:1129-1135.

PMID: 30809094 PMC: 6376880. DOI: 10.2147/OTT.S188820.

In silico discovery of a FOXM1 driven embryonal signaling pathway in therapy resistant neuroblastoma tumors.

Vanhauwaert S, Decaesteker B, De Brouwer S, Leonelli C, Durinck K, Mestdagh P Sci Rep. 2018; 8(1):17468.

PMID: 30504901 PMC: 6269481. DOI: 10.1038/s41598-018-35868-5.

References

Bar-Shira A, Pinthus J, Rozovsky U, Goldstein M, Sellers W, Yaron Y . Multiple genes in human 20q13 chromosomal region are involved in an advanced prostate cancer xenograft. Cancer Res. 2002; 62(23):6803-7. View

Tarasov K, Tarasova Y, Tam W, Riordon D, Elliott S, Kania G . B-MYB is essential for normal cell cycle progression and chromosomal stability of embryonic stem cells. PLoS One. 2008; 3(6):e2478. PMC: 2423619. DOI: 10.1371/journal.pone.0002478. View

Galderisi U, Di Bernardo G, Cipollaro M, Peluso G, Cascino A, Cotrufo R . Differentiation and apoptosis of neuroblastoma cells: role of N-myc gene product. J Cell Biochem. 1999; 73(1):97-105. DOI: 10.1002/(sici)1097-4644(19990401)73:1<97::aid-jcb11>3.0.co;2-m. View

Chayka O, Corvetta D, Dews M, Caccamo A, Piotrowska I, Santilli G . Clusterin, a haploinsufficient tumor suppressor gene in neuroblastomas. J Natl Cancer Inst. 2009; 101(9):663-77. PMC: 2720718. DOI: 10.1093/jnci/djp063. View

Gustafson W, Weiss W . Myc proteins as therapeutic targets. Oncogene. 2010; 29(9):1249-59. PMC: 2904682. DOI: 10.1038/onc.2009.512. View

Schwab R, Bussolari R, Corvetta D, Chayka O, Santilli G, Kwok J . Isolation and functional assessment of common, polymorphic variants of the B-MYB proto-oncogene associated with a reduced cancer risk. Oncogene. 2007; 27(20):2929-33. DOI: 10.1038/sj.onc.1210947. View

Cervellera M, Raschella G, Santilli G, Tanno B, Ventura A, Mancini C . Direct transactivation of the anti-apoptotic gene apolipoprotein J (clusterin) by B-MYB. J Biol Chem. 2000; 275(28):21055-60. DOI: 10.1074/jbc.M002055200. View

Schwab R, Caccamo A, Bettuzzi S, Anderson J, Sala A . B-MYB is hypophosphorylated and resistant to degradation in neuroblastoma: implications for cell survival. Blood Cells Mol Dis. 2007; 39(3):263-71. DOI: 10.1016/j.bcmd.2007.04.006. View

Nakajima T, Yasui K, Zen K, Inagaki Y, Fujii H, Minami M . Activation of B-Myb by E2F1 in hepatocellular carcinoma. Hepatol Res. 2008; 38(9):886-95. DOI: 10.1111/j.1872-034X.2008.00324.x. View

10.

Sala A . B-MYB, a transcription factor implicated in regulating cell cycle, apoptosis and cancer. Eur J Cancer. 2005; 41(16):2479-84. DOI: 10.1016/j.ejca.2005.08.004. View

11.

Zhu W, Giangrande P, Nevins J . E2Fs link the control of G1/S and G2/M transcription. EMBO J. 2004; 23(23):4615-26. PMC: 533046. DOI: 10.1038/sj.emboj.7600459. View

12.

TANNER M, Grenman S, Koul A, Johannsson O, Meltzer P, Pejovic T . Frequent amplification of chromosomal region 20q12-q13 in ovarian cancer. Clin Cancer Res. 2000; 6(5):1833-9. View

13.

Maris J, Hogarty M, Bagatell R, Cohn S . Neuroblastoma. Lancet. 2007; 369(9579):2106-20. DOI: 10.1016/S0140-6736(07)60983-0. View

14.

Nakagoshi H, Sawazaki T, Mizuguchi G, Ishii S . Transcriptional activation of the c-myc gene by the c-myb and B-myb gene products. Oncogene. 1992; 7(6):1233-40. View

15.

Rhodes D, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D . ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia. 2004; 6(1):1-6. PMC: 1635162. DOI: 10.1016/s1476-5586(04)80047-2. View

16.

Lang G, White J, Argent-Katwala M, Allinson C, Weston K . Myb proteins regulate the expression of diverse target genes. Oncogene. 2004; 24(8):1375-84. DOI: 10.1038/sj.onc.1208301. View

17.

Nakano I, Paucar A, Bajpai R, Dougherty J, Zewail A, Kelly T . Maternal embryonic leucine zipper kinase (MELK) regulates multipotent neural progenitor proliferation. J Cell Biol. 2005; 170(3):413-27. PMC: 2171475. DOI: 10.1083/jcb.200412115. View

18.

Brodeur G . Significance of intratumoral genetic heterogeneity in neuroblastomas. Med Pediatr Oncol. 2002; 38(2):112-3. DOI: 10.1002/mpo.1282. View

19.

Meyer N, Penn L . Reflecting on 25 years with MYC. Nat Rev Cancer. 2008; 8(12):976-90. DOI: 10.1038/nrc2231. View

20.

Garcia P, Frampton J . The transcription factor B-Myb is essential for S-phase progression and genomic stability in diploid and polyploid megakaryocytes. J Cell Sci. 2006; 119(Pt 8):1483-93. DOI: 10.1242/jcs.02870. View