SATB1募集p300/CBP调控乳酸脱氢酶促进卵巢癌转移的机制研究

Metastasis is the main cause of death in patients with epithelial ovarian cancer. Our previous study found that special AT-rich sequence binding protein 1 (SATB1) was involved in multiple gene transcription and post-transcriptional modification, its high expression was associated with the high metastasis rate and low survival rate of epithelial ovarian cancer. Our pre-experiment showed that knockdown SATB1 expression in ovarian cancer could down-regulate the expression and activity of the key glycolytic enzyme - lactic acid dehydrogenase (LDH), inhibit the production of the main energy source of cells - lactate, and the high expression level of LDH was associated with high metastasis and poor prognosis of ovarian cancer. Further studies found that SATB1 can recruit acetylase - p300/CBP, and there are multiple acetylation and transcription factor loci on LDH gene. Therefore, we speculate that there is a SATB1-p300/CBP-LDH-lactate regulation pathway in epithelial ovarian cancer: SATB1 recruits p300/CBP and promotes LDH expression and lactic acid production through transcriptional and post-transcriptional modification, so as to promote ovarian cancer metastasis. Based on previous studies, we will use molecular biology experiments such as Co-IP, Chip and reporter genes to elucidate the mechanism of SATB1 regulation of LDH expression in ovarian cancer, participation in lactate metabolism, and to provide theoretical basis for individualized targeting therapy of ovarian cancer.

转移是上皮性卵巢癌患者致死的主要原因。课题组前期研究发现：特异AT序列结合蛋白1(SATB1)参与多个基因的转录和转录后修饰，其高表达与卵巢癌高转移率和低生存率相关，预实验发现：干扰卵巢癌细胞SATB1表达，可下调乳酸代谢关键酶-乳酸脱氢酶(LDH)表达和活性，抑制细胞主要能量来源-乳酸的产生，且高水平的LDH与卵巢癌的高转移和差预后相关，进一步研究发现SATB1能募集乙酰化酶p300/CBP，同时LDH基因上存在多个乙酰化和转录因子位点。因此我们推测，上皮性卵巢癌中存在SATB1-p300/CBP-LDH-乳酸调控通路：SATB1募集p300/CBP通过转录及转录后修饰促进LDH表达及乳酸生成，促进卵巢癌转移。本课题拟在前期研究基础上，采用Co-IP，Chip及报告基因等分子生物学实验来揭示SATB1调控卵巢癌LDH表达，参与乳酸代谢促进其转移的机制，为卵巢癌个体化靶向治疗提供理论依据。

上皮性卵巢癌（EOC）其侵袭转移和易耐药的特性，是直接导致预后差，死亡率高的主要原因。课题组前期研究发现:特异AT序列结合蛋白1( SATB1)参与多个基因的转录和转录后修饰，其高表达与卵巢癌高转移率和低生存率相关，因此我们推测，上皮性卵巢癌中存在SATB1-LDH-乳酸调控通路促进卵巢癌转移。本研究中我们发现SATB1可以通过调节糖酵解关键激酶LDH以及MCT1的水平参与乳酸代谢的调控，增加细胞主要能量来源-乳酸的分泌，促进卵巢癌细胞增殖。同时临床病理资料也显示在卵巢癌患者血清中LDH呈高水平表达，并且观察到血清LDH水平与临床卵巢癌患者在高等级，高阶段，非满意切除也有统计学上的增加，与预后负相关，结果显示出LDH在EOC进展转移中具有重要作用。近年来，PARP抑制剂大幅改善了卵巢癌患者预后，但对于野生型BRCA患者疗效欠佳。我们在研究中也发现LDH-A的表达水平可以显著影响PARP抑制剂对野生型BRCA卵巢癌的抑制作用，PARP抑制剂处理增加了SKOV3细胞中的LDH-A水平，使用Oxamate抑制LDH-A后，SKOV3细胞增殖、迁移和侵袭能力均受到抑制。PARP抑制剂和LDH-A抑制的联合治疗显示出协同抑癌作用，结果表明，即使在PARP抑制剂效果不理想的情况下，Oxamate作为补救措施，也能有效抑制肿瘤进展，改善肿瘤预后。最后我们也回顾了PARP抑制剂耐药机制，分析了HRD评分在PARP抑制剂治疗卵巢癌预后预测中的作用价值。综上，我们证实了SATB1可以通过 LDH参与卵巢癌细胞乳酸代谢调控，促进其转移。尤其是LDH在上皮性卵巢癌的进展中扮演着重要的角色，LDH-A的表达水平可能是影响野生型BRCA卵巢癌患者对PARP抑制剂不敏感的分子机制之一。LDH-A和PARP抑制剂的联合治疗代表了一种有前途的治疗方法，可能为BRCA无突变的卵巢癌患者提供一种新的治疗策略。.项目研究成果在《Frontiers in Molecular Biosciences 》《BMC Cancer》《AGING》《Translational Cancer Research》《Environmental Science and Pollution Research 》等期刊发表论文5篇。