Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma.

نویسندگان

  • Daniel R Carter
  • Jayne Murray
  • Belamy B Cheung
  • Laura Gamble
  • Jessica Koach
  • Joanna Tsang
  • Selina Sutton
  • Heyam Kalla
  • Sarah Syed
  • Andrew J Gifford
  • Natalia Issaeva
  • Asel Biktasova
  • Bernard Atmadibrata
  • Yuting Sun
  • Nicolas Sokolowski
  • Dora Ling
  • Patrick Y Kim
  • Hannah Webber
  • Ashleigh Clark
  • Michelle Ruhle
  • Bing Liu
  • André Oberthuer
  • Matthias Fischer
  • Jennifer Byrne
  • Federica Saletta
  • Le Myo Thwe
  • Andrei Purmal
  • Gary Haderski
  • Catherine Burkhart
  • Frank Speleman
  • Katleen De Preter
  • Anneleen Beckers
  • David S Ziegler
  • Tao Liu
  • Katerina V Gurova
  • Andrei V Gudkov
  • Murray D Norris
  • Michelle Haber
  • Glenn M Marshall
چکیده

Amplification of the MYCN oncogene predicts treatment resistance in childhood neuroblastoma. We used a MYC target gene signature that predicts poor neuroblastoma prognosis to identify the histone chaperone FACT (facilitates chromatin transcription) as a crucial mediator of the MYC signal and a therapeutic target in the disease. FACT and MYCN expression created a forward feedback loop in neuroblastoma cells that was essential for maintaining mutual high expression. FACT inhibition by the small-molecule curaxin compound CBL0137 markedly reduced tumor initiation and progression in vivo. CBL0137 exhibited strong synergy with standard chemotherapy by blocking repair of DNA damage caused by genotoxic drugs, thus creating a synthetic lethal environment in MYCN-amplified neuroblastoma cells and suggesting a treatment strategy for MYCN-driven neuroblastoma.

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

Combined IFN-; and retinoic acid treatment targets the N-Myc/Max/Mad1 network resulting in repression of N-Myc target genes in MYCN-amplified neuroblastoma cells

The MYCN protooncogene is involved in the control of cell proliferation, differentiation, and survival of neuroblasts. Deregulation of MYCN by gene amplification contributes to neuroblastoma development and is strongly correlated to advanced disease and poor outcome, emphasizing the urge for new therapeutic strategies targeting MYCN function. The transcription factor N-Myc, encoded by MYCN, reg...

متن کامل

Comparison of the Initial Treatment Results of N-myc Positive and N-myc Negative Neuroblastoma Patients

Background: Neuroblastoma is the most common extra cranial malignant solid tumor of childhood. Various molecular and cytogenetic factors have been implicated in the pathogenesis of neuroblastoma, some of which have proven useful in predicting clinical behavior. Over expression of the oncogen N-myc, is an important indicator of prognosis. Materials and Methods: Our study was performed from 20...

متن کامل

Effect of valproic acid on JAK/STAT pathway, SOCS1, SOCS3, Bcl-xL, c-Myc, and Mcl-1 gene expression, cell growth inhibition and apoptosis induction in human colon cancer HT29 cell line.

Background and aim: Cytokines are a large family of protein messengers. These proteins induce various cellular responses. Janus kinases (JAKs) are mediators of cytokine, activated JAKs phosphorylate signal transducers, and activators of transcription (STAT) proteins that regulate cell differentiation, proliferation, and apoptosis. Aberrant JAK/STAT signaling is involved in the oncogenesis of se...

متن کامل

Combined IFN-gamma and retinoic acid treatment targets the N-Myc/Max/Mad1 network resulting in repression of N-Myc target genes in MYCN-amplified neuroblastoma cells.

The MYCN protooncogene is involved in the control of cell proliferation, differentiation, and survival of neuroblasts. Deregulation of MYCN by gene amplification contributes to neuroblastoma development and is strongly correlated to advanced disease and poor outcome, emphasizing the urge for new therapeutic strategies targeting MYCN function. The transcription factor N-Myc, encoded by MYCN, reg...

متن کامل

Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas.

We investigated the transcriptional and epigenetic repression of miR-29 by MYC, HDAC3, and EZH2 in mantle cell lymphoma and other MYC-associated lymphomas. We demonstrate that miR-29 is repressed by MYC through a corepressor complex with HDAC3 and EZH2. MYC contributes to EZH2 upregulation via repression of the EZH2 targeting miR-26a, and EZH2 induces MYC via inhibition of the MYC targeting miR...

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:
  • Science translational medicine

دوره 7 312  شماره 

صفحات  -

تاریخ انتشار 2015