Table_1_MKL1 Mediates TGF-β Induced RhoJ Transcription to Promote Breast Cancer Cell Migration and Invasion.doc

Differential regulation of gene transcription contributes to cancer metastasis. We investigated the involvement of a Rho GTPase (RhoJ) in breast cancer metastasis focusing on the mechanism underlying RhoJ trans-activation by pro-metastatic cues. We report that expression of RhoJ was up-regulated in malignant breast cancer cells compared to more benign ones. Higher RhoJ expression was also detected in human breast cancer biopsy specimens of advanced stages. RhoJ depletion attenuated breast cancer cell migration and invasion in vitro and metastasis in vivo. The pro-metastatic stimulus TGF-β activated RhoJ via megakaryocytic leukemia 1 (MKL1). MKL1 interacted with and was recruited by ETS-related gene 1 (ERG1) to the RhoJ promoter to activate transcription. In conclusion, our data delineate a novel transcriptional pathway that contributes to breast cancer metastasis. Targeting the ERG1-MKL1-RhoJ axis may be considered as a reasonable approach to treat malignant breast cancer.

基因转录差异调控是肿瘤转移的重要机制。本研究聚焦于促转移信号引发的Rho GTPase（RhoJ）在乳腺癌转移中的参与情况及其作用机制。研究发现，相较于良性乳腺癌细胞，恶性乳腺癌细胞中RhoJ的表达上调。在晚期乳腺癌活检标本中，也检测到RhoJ的高表达。RhoJ的耗竭可显著降低乳腺癌细胞在体外迁移和侵袭能力，以及体内转移。促转移刺激因子TGF-β通过巨核细胞白血病1（MKL1）激活RhoJ。MKL1与ETS相关基因1（ERG1）相互作用并被其招募至RhoJ启动子区域，从而激活转录。总之，我们的数据描绘了一条新的转录途径，该途径对乳腺癌转移具有重要作用。针对ERG1-MKL1-RhoJ轴作为治疗恶性乳腺癌的潜在策略值得考虑。