Moinova Helen R, Chen Wei-Dong, Shen Lanlan, Smiraglia Dominic, Olechnowicz Joseph, Ravi Lakshmeswari, Kasturi Lakshmi, Myeroff Lois, Plass Christoph, Parsons Ramon, Minna John, Willson James K V, Green Sylvan B, Issa Jean-Pierre, Markowitz Sanford D
Cancer Center and Department of Medicine at Case Western Reserve University, Cleveland, OH 44106, USA.
Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4562-7. doi: 10.1073/pnas.062459899. Epub 2002 Mar 19.
Chromatin remodeling enzymes are increasingly implicated in a variety of important cellular functions. Various components of chromatin remodeling complexes, including several members of the SWI/SNF family, have been shown to be disrupted in cancer. In this study we identified as a target for gene inactivation in colon cancer the gene for helicase-like transcription factor (HLTF), a SWI/SNF family protein. Loss of HLTF expression accompanied by HLTF promoter methylation was noted in nine of 34 colon cancer cell lines. In these cell lines HLTF expression was restored by treatment with the demethylating agent 5-azacytidine. In further studies of primary colon cancer tissues, HLTF methylation was detected in 27 of 63 cases (43%). No methylation of HLTF was detected in breast or lung cancers, suggesting selection for HLTF methylation in colonic malignancies. Transfection of HLTF suppressed 75% of colony growth in each of three different HLTF-deficient cell lines, but showed no suppressive effect in any of three HLTF-proficient cell lines. These findings show that HLTF is a common target for methylation and epigenetic gene silencing in colon cancer and suggest HLTF is a candidate colon cancer suppressor gene.
染色质重塑酶越来越多地参与多种重要的细胞功能。染色质重塑复合物的各种成分，包括SWI/SNF家族的几个成员，已被证明在癌症中被破坏。在本研究中，我们确定解旋酶样转录因子（HLTF）基因是结肠癌基因失活的一个靶点，HLTF是一种SWI/SNF家族蛋白。在34个结肠癌细胞系中的9个中发现HLTF表达缺失并伴有HLTF启动子甲基化。在这些细胞系中，用去甲基化剂5-氮杂胞苷处理可恢复HLTF表达。在对原发性结肠癌组织的进一步研究中，63例中有27例（43%）检测到HLTF甲基化。在乳腺癌或肺癌中未检测到HLTF甲基化，提示结肠恶性肿瘤中存在HLTF甲基化的选择。HLTF转染抑制了三种不同HLTF缺陷细胞系中每一种的75%的集落生长，但在三种HLTF正常的细胞系中均未显示出抑制作用。这些发现表明HLTF是结肠癌甲基化和表观遗传基因沉默的常见靶点，并提示HLTF是一种候选的结肠癌抑癌基因。
