CDCA7L functions as a male-specific oncogene in astrocytoma

Wednesday, September 24, 2014 — Poster Session IV
10:00 a.m. –12:00 p.m.	FAES Academic Center	NCI	CANCER-14

* FARE Award Winner

Authors

• M.H. Lee
• K.M. Reilly

Abstract

The most common primary brain tumors, astrocytoma/glioblastoma multiforme (GBM), show male predominance. To identify male-specific gliomagenesis modifier(s), we performed linkage analysis in Nf1-/+;Trp53-/+cis (NPcis) mouse model of astrocytoma/GBM and used combinatorial bioinformatics approaches and cross-species comparisons. Here, we show that CDCA7L is a male-specific oncogene in astrocytoma/GBM. CDCA7L expression was up-regulated in astrocytoma/GBM cells compared to normal brain, with males showing higher than females. CDCA7L knockdown decreased growth/viability of male-derived astrocytoma cells, but not females. Further studies showed that CDCA7L depletion in male-derived astrocytoma cells induced cleaved Caspase-3 and p27 expression and reduced CyclinD1 expression. Furthermore, Cdca7l overexpression promoted growth of WT mouse primary astrocytes only in males by inducing CyclinD1 expression, suggesting male-specific oncogenic role for CDCA7L in astrocytoma/GBM. Strikingly, CDCA7L depletion in human female U87MG GBM cells increased growth/viability opposite to males. Because male-female differences in CDCA7L action were hormone-independent, we examined whether the male-specific histone demethylase KDM5D regulates CDCA7L’s effects. We found that KDM5D knockdown inhibited male-specific effects of CDCA7L on p27/CyclinD1 expression. Our data highlight sex-specificity of CDCA7L in astrocytoma/GBM tumorigenesis and show that CDCA7L mechanism is oncogenic in males, while being neutral or tumor suppressive in females. This has important implications for human GBM treatment.

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