Department of Biochemistry and Molecular Medicine, University of California at Davis, Sacramento, CA 95817, USA.
Mol Cancer Res. 2010 Feb;8(2):183-93. doi: 10.1158/1541-7786.MCR-09-0095. Epub 2010 Feb 2.
The proto-oncogene ACTR/AIB1, a coactivator for transcription factors such as the nuclear receptors and E2Fs, is frequently overexpressed in various cancers including breast cancers. However, the underlying mechanism is poorly understood. Here, we identified several functional, noncanonical E2F binding sites in the ACTR first exon and intron that are critical for ACTR gene activation. We also found that the newly identified AAA+ coregulator AAA+ nuclear coregulator cancer associated (ANCCA) is recruited to the ACTR promoter and directly controls ACTR expression in breast cancer cells. Importantly, immunohistochemistry analysis indicated that ACTR overexpression is highly correlated with the expression of E2F1 and ANCCA in a cohort of human primary and lymph node-metastasized breast cancer specimens. Along with previous findings from us and others that ACTR is involved in its own gene regulation, these results suggest that one major mechanism of ACTR overexpression in cancer is the concerted, aberrant function of the nuclear coregulators such as ANCCA and ACTR, and they point to therapeutic strategies that target the Rb-E2F axis and/or the coregulator ANCCA for ACTR-overexpressing cancers.
原癌基因 ACTR/AIB1 是转录因子（如核受体和 E2Fs）的共激活因子，在包括乳腺癌在内的各种癌症中经常过表达。然而，其潜在机制尚不清楚。在这里，我们在 ACTR 的第一个外显子和内含子中鉴定了几个功能上的、非典型的 E2F 结合位点，这些结合位点对于 ACTR 基因的激活至关重要。我们还发现，新鉴定的 AAA+ 共激活因子 AAA+核共激活因子癌症相关（ANCCA）被招募到 ACTR 启动子，并直接控制乳腺癌细胞中的 ACTR 表达。重要的是，免疫组织化学分析表明，在一组人类原发性和淋巴结转移乳腺癌标本中，ACTR 的过表达与 E2F1 和 ANCCA 的表达高度相关。结合我们和其他人之前的发现，即 ACTR 参与自身基因调控，这些结果表明，癌症中 ACTR 过表达的一个主要机制是核共激活因子（如 ANCCA 和 ACTR）的协同、异常功能，并且它们指出了针对 Rb-E2F 轴和/或共激活因子 ANCCA 的治疗策略，适用于 ACTR 过表达的癌症。
