Role of the chromobox protein CBX7 in lymphomagenesis

Abstract

Chromobox 7 (CBX7) is a chromobox family protein and a component of the Polycomb repressive complex 1 (PRC1) that extends the lifespan of cultured epithelial cells and can act independently of BMI-1 to repress the INK4a/ARF tumor suppressor locus. To determine whether CBX7 might be oncogenic, we examined its expression pattern in a range of normal human tissues and tumor samples. CBX7 was expressed at high levels in germinal center lymphocytes and germinal center-derived follicular lymphomas, where elevated expression correlated with high c-Myc expression and a more advanced tumor grade. By targeting Cbx7 expression to the lymphoid compartment in mice, we showed that Cbx7 can initiate T cell lymphomagenesis and cooperate with c-Myc to produce highly aggressive B cell lymphomas. Furthermore, Cbx7 repressed transcription from the Ink4a/Arf locus and acted epistatically to the Arf-p53 pathway during tumorigenesis. These data identify CBX7 as a chromobox protein causally linked to cancer development and may help explain the low frequency of INK4a/ ARF mutations observed in human follicular lymphoma.Ink4a-ARF ͉ oncogene ͉ Polycomb ͉ follicular lymphoma ͉ p53

Mitogen-activated Protein Kinase Signaling Mediates Phosphorylation of Polycomb Ortholog Cbx7

“…This suggests that the Thr-118 phosphorylation motif holds important function and will be interesting to examine further in the context of cancer, particularly those tumors driven by ERK signaling, such as melanoma. To date, CBX7 has been implicated as an oncogene in prostate cancer and lymphoma, as well as a tumor suppressor in lung and breast cancer (17,18,58,59). Consistent with this, we noted a loss of Cbx7 expression (and T118ph) in a series of mouse mammary carcinoma cells with increasing metastatic ability.…”

“…A functional role for Cbx7 in the context of cell cycle regulation was identified through a genetic screen that uncovered Cbx7 as a repressor of the INK4a/ARF locus, allowing bypass of senescence in primary human fibroblasts (16). Studies in prostate cancer and lymphoma have demonstrated its role as an oncogene (17,18). In a developmental context, we and others have recently reported Cbx7 to be the predominant Pc protein expressed in mouse ES cells, where it acts to maintain self-renewal and pluripotency (19,20).…”

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16INK4a

“…Much less is known about how the function and expression of the PRCs and their components are controlled. The regulation of CBX7 is particularly interesting because CBX7 is implicated in senescence (Gil et al ., 2004) and cancer (Bernard et al ., 2005; Scott et al ., 2007; Pallante et al ., 2008; Karamitopoulou et al ., 2010). In addition, CBX7 levels and consequently the composition of PRC1 complexes change dramatically during ES cell differentiation (Morey et al ., 2012; O'Loghlen et al ., 2012).…”

Cancer epigenetics: linking basic biology to clinical medicine

“…CBX7, another PcG protein, is a constituent of PRC1, and has also been shown to read the repressive histone marks, H3K9me3 and H3K27me3, and to participate in mediating gene silencing in the development of cancer [98,[110][111][112]. Similar to EZH2, in an experimental setting, CBX7 is able to recruit DNA methylation machinery to gene promoters and facilitate repression of genes, which are frequently silenced in adult cancer [98].…”