Enhanced growth and proliferation of cancer cells are accompanied by profound changes in cellular metabolism. These metabolic changes are also common under physiological conditions, and include increased glucose fermentation accompanied by elevated cytosolic pH (pHc)^1,2. However, how these changes contribute to enhanced cell growth and proliferation is unclear. Here, we show that elevated pHc specifically orchestrates an E2F-dependent transcriptional programme to drive cell proliferation by promoting cyclin D1 expression. pHc-dependent transcription of cyclin D1 requires the transcription factors CREB1, ATF1 and ETS1, and the histone acetyltransferases p300 and CBP. Biochemical characterization revealed that the CREB1–p300/CBP interaction acts as a pH sensor and coincidence detector, integrating different mitotic signals to regulate cyclin D1 transcription. We also show that elevated pHc contributes to increased cyclin D1 expression in malignant pleural mesotheliomas (MPMs), and renders these cells hypersensitive to pharmacological reduction of pHc. Taken together, these data demonstrate that elevated pHc is a critical cellular signal regulating G1 progression, and provide a mechanism linking elevated pHc to oncogenic activation of cyclin D1 in MPMs, and possibly other cyclin D1~dependent tumours. Thus, an increase of pHc may represent a functionally important, early event in the aetiology of cancer that is amenable to therapeutic intervention.

癌细胞生长和增殖的增强伴随着细胞代谢的深刻变化。这些代谢变化在生理条件下也很常见，包括增加的葡萄糖发酵伴随着升高的细胞溶质 pH (pHc) ^1,2. 然而，这些变化如何促进细胞生长和增殖尚不清楚。在这里，我们显示升高的 pHc 专门协调了一个依赖 E2F 的转录程序，通过促进细胞周期蛋白 D1 的表达来驱动细胞增殖。cyclin D1 的 pHc 依赖性转录需要转录因子 CREB1、ATF1 和 ETS1，以及组蛋白乙酰转移酶 p300 和 CBP。生化表征显示 CREB1-p300/CBP 相互作用充当 pH 传感器和巧合检测器，整合不同的有丝分裂信号来调节细胞周期蛋白 D1 转录。我们还表明，升高的 pHc 有助于增加恶性胸膜间皮瘤 (MPM) 中的细胞周期蛋白 D1 表达，并使这些细胞对 pHc 的药理学降低过敏。综合起来，这些数据表明，升高的 pHc 是调节 G1 进展的关键细胞信号，并提供了一种机制，将升高的 pHc 与 MPM 中细胞周期蛋白 D1 的致癌激活联系起来，可能还有其他细胞周期蛋白 D1 依赖性肿瘤。因此，pHc 的增加可能代表了癌症病因学中一个功能上重要的早期事件，该事件可以接受治疗干预。