Gururaj Anupama E, Singh Rajesh R, Rayala Suresh K, Holm Caroline, den Hollander Petra, Zhang Hao, Balasenthil Seetharaman, Talukder Amjad H, Landberg Goran, Kumar Rakesh
Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6670-5. doi: 10.1073/pnas.0601989103. Epub 2006 Apr 14.
Here we define a function of metastasis-associated protein 1 (MTA1), a presumed corepressor of estrogen receptor alpha (ERalpha), as a transcriptional activator of Breast Cancer Amplified Sequence 3 (BCAS3), a gene amplified and overexpressed in breast cancers. We identified BCAS3 as a MTA1 chromatin target in a functional genomic screen. MTA1 stimulation of BCAS3 transcription required ERalpha and involved a functional ERE half-site in BCAS3. Furthermore, we discovered that MTA1 is acetylated on lysine 626, and that this acetylation is necessary for a productive transcriptional recruitment of RNA polymerase II complex to the BCAS3 enhancer sequence. BCAS3 expression was elevated in mammary tumors from MTA1 transgenic mice and 60% of the human breast tumors, and correlated with the coexpression of MTA1 as well as with tumor grade and proliferation of primary breast tumor samples. These findings reveal a previously unrecognized function of MTA1 in stimulating BCAS3 expression and suggest an important role for MTA1-BCAS3 pathway in promoting cancerous phenotypes in breast tumor cells.
在这里，我们将转移相关蛋白1（MTA1）（一种假定的雌激素受体α（ERα）共抑制因子）定义为乳腺癌扩增序列3（BCAS3）的转录激活因子，BCAS3是一种在乳腺癌中扩增并过表达的基因。在功能基因组筛选中，我们将BCAS3鉴定为MTA1的染色质靶点。MTA1对BCAS3转录的刺激需要ERα，并涉及BCAS3中的一个功能性雌激素反应元件（ERE）半位点。此外，我们发现MTA1在赖氨酸626处被乙酰化，并且这种乙酰化对于RNA聚合酶II复合物有效转录募集到BCAS3增强子序列是必需的。在MTA1转基因小鼠的乳腺肿瘤和60%的人类乳腺肿瘤中，BCAS3表达升高，并且与MTA1的共表达以及原发性乳腺肿瘤样本的肿瘤分级和增殖相关。这些发现揭示了MTA1在刺激BCAS3表达方面以前未被认识的功能，并表明MTA1 - BCAS3途径在促进乳腺肿瘤细胞的癌性表型中起重要作用。
