ANCCA, a novel nuclear cofactor, is overexpressed in breast cancer and possesses oncogenic potential

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ANCCA (AAA+ Nuclear Coactivator Cancer Associated) was recently identified by us as a target gene of the nuclear hormone receptor coactivator/proto-oncogene ACTR/AIB1. Our further study showed that ANCCA plays an important role in hormone-dependent breast cancer cell proliferation and can act as an estrogen receptor (ERα) coactivator to mediate estrogen-stimulated expression of key cell proliferation regulators such as cyclin D1 and c-myc.
 Here we show that high levels of ANCCA are required for ER-negative cancer cell proliferation. We demonstrated that knockdown of ANCCA through siRNA severely inhibited the proliferation of a number of cancer cell lines, which correlated with a significant decrease in S-phase population and the down-regulation of expression of major cell cycle regulators. Since most of affected genes were targets of pRb-E2F, we examined the possible, direct role of ANCCA as a cell cycle regulator. We found that ANCCA is recruited, in cell cycle dependent manner, to promoters of E2F target-genes. Our sequential ChIP assay showed that ANCCA is co-recruited with E2F to these promoters. Interestingly, we also found that ANCCA expression is cell cycle-regulated, and it involved E2F. These findings strongly suggested that ANCCA is an E2F coactivator and play an important function in control of cell cycle gene expression.
 To further study the role of ANCCA in cancer, we examined its expression by IHC on the panel of human breast cancer samples. Analysis revealed that ANCCA is frequently overexpressed in both ER-positive and ER-negative tumors and that expression level of ANCCA appeared to correlate closely with tumor cell proliferation based on the Ki67 index. Taking together, our findings suggest that ANCCA is novel E2F and ER coregulator with an oncogenic potential. Its ATPase function makes ANCCA an attractive target for small-molecule based anti-cancer therapy.