TC10-like (TCL) is a small GTPase that has been implicated in carcinogenesis. Elevated TCL expression has been observed in many different types of cancers although the underlying epigenetic mechanism is poorly understood. Here we report that TCL up-regulation was associated with high malignancy in both human colorectal cancer biopsy specimens and in cultured colorectal cancer cells. Hypoxia, a pro-metastatic stimulus, up-regulated TCL expression in HT-29 cells. Further studies revealed that myocardin-related transcription factor A (MRTF-A) promoted migration and invasion of HT-29 cells in a TCL-dependent manner. MRTF-A directly bound to the proximal TCL promoter in response to hypoxia to activate TCL transcription. Chromatin immunoprecipitation (ChIP) assay showed that hypoxia stimulation specifically enhanced acetylation of histone H4K16 surrounding the TCL promoter, which was abolished by MRTF-A depletion or inhibition. Mechanistically, MRTF-A interacted with and recruited the H4K16 acetyltransferase hMOF to the TCL promoter to cooperatively regulate TCL transcription. hMOF depletion or inhibition attenuated hypoxia-induced TCL expression and migration/invasion of HT-29 cells. In conclusion, our data identify a novel MRTF-A-hMOF-TCL axis that contributes to colorectal cancer metastasis.

TC10 样 (TCL) 是一种小 GTP 酶，与致癌作用有关。尽管对潜在的表观遗传机制知之甚少，但已在许多不同类型的癌症中观察到 TCL 表达升高。在这里，我们报告了 TCL 上调与人类结直肠癌活检标本和培养的结直肠癌细胞中的高度恶性相关。缺氧，一种促转移刺激，上调 HT-29 细胞中的 TCL 表达。进一步的研究表明，心肌素相关转录因子 A（MRTF-A）以 TCL 依赖性方式促进 HT-29 细胞的迁移和侵袭。MRTF-A 响应缺氧直接与近端 TCL 启动子结合以激活 TCL 转录。染色质免疫沉淀 (ChIP) 测定表明，缺氧刺激特异性增强了 TCL 启动子周围组蛋白 H4K16 的乙酰化，这被 MRTF-A 消耗或抑制所消除。从机制上讲，MRTF-A 与 H4K16 乙酰转移酶 hMOF 相互作用并将其募集到 TCL 启动子以协同调节 TCL 转录。hMOF 消耗或抑制减弱了缺氧诱导的 TCL 表达和 HT-29 细胞的迁移/侵袭。总之，我们的数据确定了一种有助于结直肠癌转移的新型 MRTF-A-hMOF-TCL 轴。hMOF 消耗或抑制减弱了缺氧诱导的 TCL 表达和 HT-29 细胞的迁移/侵袭。总之，我们的数据确定了一种有助于结直肠癌转移的新型 MRTF-A-hMOF-TCL 轴。hMOF 消耗或抑制减弱了缺氧诱导的 TCL 表达和 HT-29 细胞的迁移/侵袭。总之，我们的数据确定了一种有助于结直肠癌转移的新型 MRTF-A-hMOF-TCL 轴。