Novel regulation of nuclear factor-YB by miR-485-3p affects the expression of DNA topoisomerase IIα and drug responsiveness.

نویسندگان

  • Cheng-Fen Chen
  • Xiaolong He
  • Ahmet Dirim Arslan
  • Yin-Yuan Mo
  • William C Reinhold
  • Yves Pommier
  • William T Beck
چکیده

Nuclear factor (NF)-YB, a subunit of the transcription factor nuclear factor Y (NF-Y) complex, binds and activates CCAAT-containing promoters. Our previous work suggested that NF-YB may be a mediator of topoisomerase IIα (Top2α), working through the Top2α promoter. DNA topoisomerase II (Top2) is an essential nuclear enzyme and the primary target for several clinically important anticancer drugs. Our teniposide-resistant human lymphoblastic leukemia CEM cells (CEM/VM-1-5) express reduced Top2α protein compared with parental CEM cells. To study the regulation of Top2α during the development of drug resistance, we found that NF-YB protein expression is increased in CEM/VM-1-5 cells compared with parental CEM cells. This further suggests that increased NF-YB may be a negative regulator of Top2α in CEM/VM-1-5 cells. We asked what causes the up-regulation of NF-YB in CEM/VM-1-5 cells. We found by microRNA profiling that hsa-miR-485-3p is lower in CEM/VM-1-5 cells compared with CEM cells. MicroRNA target prediction programs revealed that the 3'-untranslated region (3'-UTR) of NF-YB harbors a putative hsa-miR-485-3p binding site. We thus hypothesized that hsa-miR-485-3p mediates drug responsiveness by decreasing NF-YB expression, which in turn negatively regulates Top2α expression. To test this, we overexpressed miR-485-3p in CEM/VM-1-5 cells and found that this led to reduced expression of NF-YB, a corresponding up-regulation of Top2α, and increased sensitivity to the Top2 inhibitors. Results in CEM cells were replicated in drug-sensitive and -resistant human rhabdomyosarcoma Rh30 cells, suggesting that our findings represent a general phenomenon. Ours is the first study to show that miR-485-3p mediates Top2α down-regulation in part by altered regulation of NF-YB.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Expression of miR-485-3p and its Target FOXD3 in Chronic Lymphocytic Leukemia

Background and Aims: Previous investigations have revealed that microRNAs (miRNAs) can function as oncogenes or tumor suppressors in chronic lymphocytic leukemia (CLL) and that the expression of miRNAs, such as miR-485-3p changes in several illnesses. This study was designed to determine the expression level of miR-485-3p and its target FOXD3 in CLL patients and controls to identify if this miR...

متن کامل

Down-regulation of miR-193b-3p and miR-376a-3p in Chronic Lymphocytic Leukemia

Background: Chronic lymphocytic leukemia (CLL) is the most common adult human leukemia. Studies revealed that microRNAs (miRNAs) can function as oncogenes or tumor suppressors in CLL and that the expression of miRNAs, such as miR-193b-3p and miR-376a-3p change in several diseases. We aimed to elucidate the changes in miR-193b-3p and miR-376a-3p expression in CLL and determine their potential as...

متن کامل

EGCG regulates the cross-talk between JWA and topoisomerase IIα in non-small-cell lung cancer (NSCLC) cells

(-)-epigallocatechin-3-gallate (EGCG) is a well-known cancer chemopreventive agent. The potential mechanisms include regulation of multiple molecules. Carcinogenesis in lung cancer is related to the imbalance of tumor suppressor and oncogene. JWA is a structurally novel microtubule-binding protein and is a potential tumor suppressor. DNA topoisomerase IIα is a nuclear enzyme that governs DNA to...

متن کامل

Iron-Responsive miR-485-3p Regulates Cellular Iron Homeostasis by Targeting Ferroportin

Ferroportin (FPN) is the only known cellular iron exporter in mammalian cells and plays a critical role in the maintenance of both cellular and systemic iron balance. During iron deprivation, the translation of FPN is repressed by iron regulatory proteins (IRPs), which bind to the 5' untranslated region (UTR), to reduce iron export and preserve cellular iron. Here, we report a novel iron-respon...

متن کامل

Downregulation of HMGB1 by miR-103a-3p Promotes Cell Proliferation, Alleviates Apoptosis and Inflammation in a Cell Model of Osteoarthritis

Background: MiR-103a-3p is a small non-coding RNA and has been reported to be involved in osteogenic proliferation and differentiation, but the role of miR-103a-3p in human osteoarthritis (OA) remains unclear. Objectives: In this study, we aimed to explore its function and molecular target in chondrocytes during OA pathogenesis. Materials an...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Molecular pharmacology

دوره 79 4  شماره 

صفحات  -

تاریخ انتشار 2011