Abstract
Diffuse intrinsic pontine glioma (DIPG) is a poor-prognosis pediatric brain tumor. No effective curative therapy is currently available and no therapeutic advances have been made in several decades. BMI-1 is a member of the multimeric protein complex Polycomb repressor complex 1. It is highly expressed in a number of diseases and malignancies and has been implicated in self-renewal of normal and cancer cells, and in DNA damage signaling. The role of BMI-1 in DIPG is largely unknown. Here, we show that BMI-1 is highly expressed in tumor tissue samples of DIPG patients and in patient-derived cancer stem-like cells. BMI-1 downregulation leads to the inhibition of DIPG patient-derived neurosphere cell proliferation, cell cycle signaling, self-renewal, telomerase expression and activity, and suppresses DIPG cell migration. Moreover, targeted inhibition of BMI-1 sensitizes DIPG cells to radiomimetic drug-induced DNA damage. Together, our data validate BMI-1 as a potential therapeutic target to treat children with DIPG.
Highlights
Brain tumors are the leading cause of cancerrelated deaths in children [1]
BMI-1 mRNA expression was significantly higher (p-value
Our results showed that BMI-1 is highly expressed in the majority of DIPG specimens tested compared to the matched normal tissue
Summary
Brain tumors are the leading cause of cancerrelated deaths in children [1]. DIPG represents 8-12% of pediatric central nervous system tumors [2, 3] and is the deadliest primary malignant brain tumors in children with a 3-year overall survival rate of 5-10% [4]. Epigenetic modulation of histone proteins plays an important role in oncogenic transformation and regulation of gene expression in many cancer types. The sequential histone modifications induced by PRC2 and PRC1 allow stable silencing of gene expression. BMI-1 has been implicated in a number of biological functions including development, cell cycle, DNA damage response, senescence, stem cell proliferation and self-renewal and cancer [12]. Several studies have shown that BMI1 is highly expressed in various cancer types and plays an oncogenic role by maintaining cancer cell stemness and self-renewal, promoting carcinogenesis, invasion and metastasis (reviewed in reference 12). We show that BMI-1 is highly expressed in DIPG and its downregulation leads to the inhibition of DIPG patientderived stem-like cell proliferation, cell cycle signaling, self-renewal, telomerase expression and activity, and to the suppression of DIPG cell migration. Our data provide strong support for BMI-1 as a therapeutic target to treat patients with DIPG
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