Global Reduction of H3K4me3 Improves Chemotherapeutic Efficacy for Pediatric Ependymomas

Abstract

BACKGROUND: Ependymomas (EPNs) are the third most common brain tumor in children. These tumors are resistant to available chemotherapeutic treatments, therefore new effective targeted therapeutics must be identified. Increasing evidence shows epigenetic alterations including histone posttranslational modifications (PTMs), are associated with malignancy, chemotherapeutic resistance and prognosis for pediatric EPNs. In this study we examined histone PTMs in EPNs and identified potential targets to improve chemotherapeutic efficacy. METHODS: Global histone H3 lysine 4 trimethylation (H3K4me3) levels were detected in pediatric EPN tumor samples with immunohistochemistry and immunoblots. Candidate genes conferring therapeutic resistance were profiled in pediatric EPN tumor samples with micro-array. Promoter H3K4me3 was examined for two candidate genes, CCND1 and ERBB2, with chromatin-immunoprecipitation coupled with real-time PCR (ChIP-PCR). These methods and MTS assay were used to verify a relationship between H3K4me3 levels and CCND1 and ERBB2, and to investigate cell viability in response to chemotherapeutic drugs in primary cultured pediatric EPN cells. RESULTS: H3K4me3 levels positively correlate with WHO grade malignancy in pediatric EPNs and are associated with progression free survival in patients with posterior fossa group A EPNs (PF-EPN-A). Reduction of H3K4me3 by silencing its methyltransferase SETD1A, in primary cultured EPN cells increased cell response to chemotherapy. CONCLUSIONS: Our results support the development of a novel treatment that targets H3K4me3 to increase chemotherapeutic efficacy in pediatric PF-EPN-A tumors.

Dietary glutamine supplementation suppresses epigenetically-activated oncogenic pathways to inhibit melanoma tumour growth

“…Our data indicate that expression of several oncogenic genes in melanoma tumours are regulated at the epigenetic level, particularly, by H3K4me3. Globally increased H3K4me3 levels have been associated with metastasis and poor prognosis in cancer 50,51 . Thus a regimen that can decrease levels of H3K4me3 would be clinically beneficial.…”

ASH2L drives proliferation and sensitivity to bleomycin and other genotoxins in Hodgkin’s lymphoma and testicular cancer cells

“…There is evidence, however, that points toward the exact opposite role of H3K4me3 in cancer progression. Decreased levels of H3K4 trimethylation levels have been suggested to be beneficial in terms of therapeutic outcome, for example in the case of pediatric ependymomas 63 . Further investigations will elucidate whether these discrepancies are due to differences between cancers derived from different tissues, the type of treatment used for these malignancies, or other factors.…”

ASH2L drives proliferation and sensitivity to bleomycin and other genotoxins in Hodgkin’s lymphoma and testicular cancer cells

“…There are studies, however, that indicate the exact opposite role of H3K4me3 in cancer progression. Decreased levels of H3K4 trimethylation levels have been suggested to be beneficial in terms of therapeutic outcome in pediatric ependymomas (53) and hepatocellular carcinoma (54). Further investigations will elucidate whether these discrepancies are due to differences between cancers derived from different tissues, the type of treatment used for these malignancies, or other factors.…”