The histone chaperone FACT promotes MYCN expression in neuroblastoma via a positive feedback loop.
Major finding: The histone chaperone FACT promotes MYCN expression in neuroblastoma via a positive feedback loop.
Clinical relevance: The FACT inhibitor CBL0137 synergizes with standard chemotherapy in neuroblastoma cells.
Impact: FACT inhibition reduces tumor initiation and progression in MYCN-driven neuroblastoma mouse models.
Neuroblastoma is a pediatric cancer in which MYCN amplification or high MYC transcriptional activity is associated with poor clinical outcome and resistance to treatment. Furthermore, transgenic MYCN expression driven by the tyrosine hydroxylase promoter (TH-MYCN mice) recapitulates many aspects of human neuroblastoma, implicating MYCN as an oncogenic driver. Therefore, targeting essential genes downstream of MYC is a potential strategy for treating high-risk neuroblastoma. Carter, Murray, and colleagues analyzed the expression of a MYC target gene signature in patient-derived neuroblastoma tumors and identified the MYC-regulated genes suppressor of Ty 16 (also known as SPT16) and structure-specific recognition protein 1 (SSRP1), which encode the heterodimeric subunits of the histone chaperone facilitates chromatin transcription (FACT) complex, as predictors of poor prognosis in neuroblastoma. MYCN bound to the promoters of both SPT16 and SSRP1 and enhanced their expression in neuroblastoma cells, and, in a feed-forward mechanism, SPT16 and SSRP1 promoted MYCN expression at both the transcriptional and posttranslational levels. Consistent with these findings, FACT was upregulated in precancerous neuroblasts of TH-MYCN mice. Treatment with the small-molecule FACT inhibitor, the curaxin compound CBL0137, decreased neuroblast hyperplasia and reduced the viability of neuroblastoma cells with high MYCN expression. In addition, CBL0137 diminished MYCN, SSRP1, and SPT16 expression in vivo, resulting in delayed tumor growth in TH-MYCN mice and long-term tumor regression, further supporting the role of FACT in MYCN-driven neuroblastoma. CBL0137 also sensitized neuroblastoma cells to DNA-damaging chemotherapy and increased the efficacy of clinically relevant chemotherapy regimens in TH-MYCN mice. CBL0137 inhibited DNA double-strand break repair after cisplatin or etoposide treatment, suggesting that the synergistic effect of CBL0137 and chemotherapy is specific to DNA-damaging agents. Together, these results indicate that inhibition of FACT suppresses MYCN activity, thereby reducing neuroblastoma tumorigenesis, and suggest that FACT inhibition has promise in combination with chemotherapy in the treatment of MYCN-driven neuroblastoma.
- ©2015 American Association for Cancer Research.