The expression of RUNDC3B is associated with promoter methylation in lymphoid malignancies

Abstract

DNA methylation is an epigenetic modification that plays an important role in the regulation of gene expression. The function of RUNDC3B has yet to be determined, although its dysregulated expression has been associated with malignant potential of both breast and lung carcinoma. To elucidate the potential of using DNA methylation in RUNDC3B as a biomarker in lymphoid malignancies, the methylation status of six regions spanning the CpG island in the promoter region of RUNDC3B was determined in cancer cell lines. Lymphoid malignancies were found to have more prominent methylation and did not express RUNDC3B compared with myeloid malignancies and solid tumours, supporting the potential use of DNA methylation in this region as a biomarker for lymphoid malignancies. RUNDC3B contains a RUN domain in its N‐terminal region that mediates interaction with Rap2, an important component of the mitogen‐activated protein kinase (MAPK) cascade, which regulates cellular proliferation and differentiation. The protein sequence of RUNDC3B also contains characteristic binding sites for MAPK intermediates. Therefore, it is possible that RUNDC3B serves as a mediator between Rap2 and the MAPK signalling cascade. Three genes with MAPK‐inducible expression were downregulated in a methylated leukaemia cell line (HSPA5, Jun and Fos). Jun and Fos combine to form the activating protein 1 transcription factor, and loss of this factor is associated with the dysregulation of genes involved in differentiation and proliferation. We hypothesize that the loss of RUNDC3B secondary to aberrant hypermethylation of the early growth response 3 transcription factor binding site results in dysregulated MAPK signalling and carcinogenesis in lymphoid malignancies. © 2015 The Authors. Hematological Oncology published by John Wiley & Sons Ltd

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“…The RPIB9 ( RUNDC3B ) gene is a candidate of a biomarker in lymphoid malignancy which possibly serves as a mediator between Rap2 and the MAPK signaling cascade [ 28 ]. Studies have indicated that the RPIB9 gene is methylated in acute myelogenous leukemia (AML) and malignant B cells and that aza-dC enhances the expression of this gene [ 29 , 30 ].…”

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“…Suggestively, the RUNDC3B gene was one of the most up-regulated genes in both cell lines—by 107-fold in C4-2B R and 174-fold in LNCaP R . The RUNDC3B gene encodes a poorly characterized protein that interacts with Rap2-binding protein 9 (RPIP9), a RAS family protein involved in the MAPK cascade pathway [ 44 ]. The RUNDC3B gene is nested in the same genetic locus as ABCB1 , with several RUNDC3B exons located in the complementary strand of the ABCB1 gene, and expression of RUNDC3B is associated with alternative regulation of the ABCB1 promoter and expression of ABCB1 mRNA isoforms [ 45 , 46 , 47 ].…”

Hematoloji̇k Mali̇gni̇teni̇n Mi̇yeloi̇d Veya Lenfoi̇d Kökeni̇ Solunum Fonksi̇yonu, Kas Kuvveti̇, Egzersi̇z Kapasi̇tesi̇ Ve Yaşam Kali̇tesi̇ni̇ Nasil Etki̇ler?

“…It has not been observed in acute myeloid leukemia (34). Therefore, RUNDC3B, expressed in various tissues such as brain, thymus, ovary, testis, leukocytes, liver, small intestines and prostate (35), is a biomarker for diagnosis and prognosis in lymphoid malignancies including acute lymphoblastic leukemia and lymphomas (32). The RUNDC3B may have a vital role in the pathogenesis of lymphoid malignancies even after allogeneic HSCT survival.…”