雌激素受体阳性乳腺癌治疗新靶点

　　组蛋白H3赖氨酸4特异性甲基转移酶（SETD1A）与基因转录激活相关，并被认为是调节三阴性乳腺癌细胞分裂周期和转移的表观遗传关键调节因子。不过，SETD1A对于雌激素受体阳性乳腺癌细胞的临床作用尚不明确。

　　2018年12月1日，国际抗癌联盟《国际癌症杂志》正式发表韩国嘉泉大学、首尔天主教大学、美国南加利福尼亚大学的研究报告，分析了SETD1A是否雌激素受体α阳性乳腺癌治疗的潜在靶点。

　　该研究发现，乳腺肿瘤组织与正常乳腺组织相比，SETD1A表达上调。此外，由SETD1A调节的雌激素受体靶基因高表达于细胞分裂周期和癌症通路。SETD1A参与组蛋白H3K4甲基化、后续雌激素受体α聚集、雌激素受体α靶基因增强子区域建立可结合染色质结构。除了雌激素受体α靶基因之外，其他细胞生存基因也可被MCF-7细胞SETD1A耗竭而下调，导致细胞增殖和迁移的显著减少，并且自发诱导细胞凋亡。该研究还发现miR-1915-3p可以作为乳腺细胞SETD1A表达的新型调节因子发挥作用。重要的是，减少SETD1A表达可以有效抑制他莫昔芬耐药乳腺癌细胞MCF-7的生长。

　　因此，该研究结果表明，SETD1A可以作为雌激素受体α阳性乳腺癌治疗的分子靶点和预后指标。

Int J Cancer. 2018 Dec 1;143(11):2871-2883.

Aberrant expression of SETD1A promotes survival and migration of estrogen receptor α-positive breast cancer cells.

Jin ML, Kim YW, Jin HL, Kang H, Lee EK, Stallcup MR, Jeong KW.

Gachon University, Incheon, Korea; Catholic University of Korea, Seoul, Korea; University of Southern California, Los Angeles, CA.

The histone H3 lysine 4-specific methyltransferase SETD1A is associated with transcription activation and is considered a key epigenetic regulator that modulates the cell cycle and metastasis in triple-negative breast cancer cells. However, the clinical role of SETD1A in estrogen receptor (ER)-positive breast cancer cells remains unclear. Here, we examined whether SETD1A is a potential target for ERα-positive breast cancer therapy. SETD1A expression was upregulated in breast tumor tissue compared to that in normal breast tissue. Moreover, ER-target genes regulated by SETD1A were particularly enriched in cell cycle and cancer pathways. SETD1A is involved in histone H3K4 methylation, subsequent recruitment of ERα, and the establishment of accessible chromatin structure at the enhancer region of ERα target genes. In addition to ERα target genes, other cell survival genes were also downregulated by SETD1A depletion in MCF-7 cells, leading to significant decrease in cell proliferation and migration, and spontaneous induction of apoptosis. We also found that miR-1915-3p functioned as a novel regulator of SETD1A expression in breast cells. Importantly, the growth of tamoxifen-resistant MCF-7 cells was effectively repressed by SETD1A knockdown. These results indicate that SETD1A may serve as a molecular target and prognostic indicator in ERα-positive breast cancer.

KEYWORDS: SETD1A; breast cancer; estrogen receptor; miR-1915-3p; tamoxifen resistance

PMID: 30191958

DOI: 10.1002/ijc.31853