Inverse Relationship between Progesterone Receptor and Myc in Endometrial Cancer.
Inverse Relationship between Progesterone Receptor and Myc in Endometrial Cancer.
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DOI：
10.1371/journal.pone.0148912
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Yang S
中科院分区：
文献类型：
--
作者：
Kavlashvili T;Jia Y;Dai D;Meng X;Thiel KW;Leslie KK;Yang S
子宫内膜癌是妇科最常见的恶性肿瘤，是一种经尿道调节的疾病。对孕酮治疗的反应与激素受体表达，特别是孕酮受体（PR）呈正相关。然而，许多晚期肿瘤失去PR表达。我们最近报道，通过将白介素与表观遗传调节剂结合，可以显著增强白介素治疗的疗效，我们称之为“分子增强白介素治疗”。目前尚不清楚的是其作用机制，以及雌激素受体α（ERα）（PR的主要诱导剂）是否是通过分子增强的孕酮治疗恢复PR功能表达所必需的。因此，我们通过产生ERα缺失的子宫内膜癌细胞系来模拟ERα和PR表达均缺失的晚期子宫内膜肿瘤。CRISPR-Cas9技术用于在基因组水平上删除ERα。我们的数据表明，使用组蛋白脱乙酰酶抑制剂（HDACi）治疗足以恢复功能性PR表达，即使在缺乏ERα的细胞中也是如此。我们的研究还显示HDACi治疗导致癌基因Myc的显著下调。我们证实，在ERα存在或不存在的情况下，PR是子宫内膜癌中Myc的负转录调节因子，这与乳腺癌细胞中的研究相反。首先，雌激素刺激增加PR表达，降低Myc在子宫内膜癌细胞系。第二，孕酮增加PR活性，但钝化Myc mRNA和蛋白表达。最后，在ERα缺失的子宫内膜癌细胞中，通过腺病毒转导PR的过表达显著降低了Myc和Myc调控基因的表达。对子宫内膜肿瘤的癌症基因组图谱（TCGA）数据库的分析确定了PR和Myc mRNA水平之间的负相关性，PR和Myc下游转录靶点SRD 5A 1、CDK 2和CCNB 1之间相应地负相关。总之，这些数据揭示了子宫内膜癌中肿瘤抑制基因PR和癌基因Myc之间先前未预料到的负相关关系。
Endometrial cancer, the most common gynecologic malignancy, is a hormonally-regulated disease. Response to progestin therapy positively correlates with hormone receptor expression, in particular progesterone receptor (PR). However, many advanced tumors lose PR expression. We recently reported that the efficacy of progestin therapy can be significantly enhanced by combining progestin with epigenetic modulators, which we term “molecularly enhanced progestin therapy.” What remained unclear was the mechanism of action and if estrogen receptor α (ERα), the principle inducer of PR, is necessary to restore functional expression of PR via molecularly enhanced progestin therapy. Therefore, we modeled advanced endometrial tumors that have lost both ERα and PR expression by generating ERα-null endometrial cancer cell lines. CRISPR-Cas9 technology was used to delete ERα at the genomic level. Our data demonstrate that treatment with a histone deacetylase inhibitor (HDACi) was sufficient to restore functional PR expression, even in cells devoid of ERα. Our studies also revealed that HDACi treatment results in marked downregulation of the oncogene Myc. We established that PR is a negative transcriptional regulator of Myc in endometrial cancer in the presence or absence of ERα, which is in contrast to studies in breast cancer cells. First, estrogen stimulation augmented PR expression and decreased Myc in endometrial cancer cell lines. Second, progesterone increased PR activity yet blunted Myc mRNA and protein expression. Finally, overexpression of PR by adenoviral transduction in ERα-null endometrial cancer cells significantly decreased expression of Myc and Myc-regulated genes. Analysis of the Cancer Genome Atlas (TCGA) database of endometrial tumors identified an inverse correlation between PR and Myc mRNA levels, with a corresponding inverse correlation between PR and Myc downstream transcriptional targets SRD5A1, CDK2 and CCNB1. Together, these data reveal a previously unanticipated inverse relationship between the tumor suppressor PR and the oncogene Myc in endometrial cancer.