Wang Qianben, Li Wei, Zhang Yong, Yuan Xin, Xu Kexin, Yu Jindan, Chen Zhong, Beroukhim Rameen, Wang Hongyun, Lupien Mathieu, Wu Tao, Regan Meredith M, Meyer Clifford A, Carroll Jason S, Manrai Arjun Kumar, Jänne Olli A, Balk Steven P, Mehra Rohit, Han Bo, Chinnaiyan Arul M, Rubin Mark A, True Lawrence, Fiorentino Michelangelo, Fiore Christopher, Loda Massimo, Kantoff Philip W, Liu X Shirley, Brown Myles
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Cell. 2009 Jul 23;138(2):245-56. doi: 10.1016/j.cell.2009.04.056.
The evolution of prostate cancer from an androgen-dependent state to one that is androgen-independent marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in androgen-independent cancers is poorly understood. We have defined the direct AR-dependent target genes in both androgen-dependent and -independent cancer cells by generating AR-dependent gene expression profiles and AR cistromes. In contrast to what is found in androgen-dependent cells, AR selectively upregulates M-phase cell-cycle genes in androgen-independent cells, including UBE2C, a gene that inactivates the M-phase checkpoint. We find that epigenetic marks at the UBE2C enhancer, notably histone H3K4 methylation and FoxA1 transcription factor binding, are present in androgen-independent cells and direct AR-enhancer binding and UBE2C activation. Thus, the role of AR in androgen-independent cancer cells is not to direct the androgen-dependent gene expression program without androgen, but rather to execute a distinct program resulting in androgen-independent growth.
前列腺癌从雄激素依赖状态发展到雄激素非依赖状态标志着其致命的进展。雄激素受体（AR）在这两种状态中都至关重要，尽管其在雄激素非依赖型癌症中的功能尚不清楚。我们通过生成AR依赖的基因表达谱和AR顺反组，确定了雄激素依赖和非依赖癌细胞中直接依赖AR的靶基因。与雄激素依赖细胞中发现的情况相反，AR在雄激素非依赖细胞中选择性地上调M期细胞周期基因，包括使M期检查点失活的UBE2C基因。我们发现，UBE2C增强子处的表观遗传标记，特别是组蛋白H3K4甲基化和FoxA1转录因子结合，存在于雄激素非依赖细胞中，并指导AR与增强子的结合以及UBE2C的激活。因此，AR在雄激素非依赖癌细胞中的作用不是在没有雄激素的情况下指导雄激素依赖的基因表达程序，而是执行一个导致雄激素非依赖生长的独特程序。
