As an essential branched amino acid, valine is pivotal for protein synthesis, neurological behaviour, haematopoiesis and leukaemia progression^1,2,3. However, the mechanism by which cellular valine abundancy is sensed for subsequent cellular functions remains undefined. Here we identify that human histone deacetylase 6 (HDAC6) serves as a valine sensor by directly binding valine through a primate-specific SE14 repeat domain. The nucleus and cytoplasm shuttling of human, but not mouse, HDAC6 is tightly controlled by the intracellular levels of valine. Valine deprivation leads to HDAC6 retention in the nucleus and induces DNA damage. Mechanistically, nuclear-localized HDAC6 binds and deacetylates ten-eleven translocation 2 (TET2) to initiate active DNA demethylation, which promotes DNA damage through thymine DNA glycosylase-driven excision. Dietary valine restriction inhibits tumour growth in xenograft and patient-derived xenograft models, and enhances the therapeutic efficacy of PARP inhibitors. Collectively, our study identifies human HDAC6 as a valine sensor that mediates active DNA demethylation and DNA damage in response to valine deprivation, and highlights the potential of dietary valine restriction for cancer treatment.

作为一种必需的支链氨基酸，缬氨酸对蛋白质合成、神经行为、造血和白血病进展至关重要^1,2,3。然而，感知细胞缬氨酸丰度以发挥后续细胞功能的机制仍未确定。在这里，我们确定人组蛋白脱乙酰酶 6 （HDAC6） 通过灵长类动物特异性 SE14 重复结构域直接结合缬氨酸来充当缬氨酸传感器。HDAC6 是人（而非小鼠）的细胞核和细胞质穿梭，受到细胞内缬氨酸水平的严格控制。缬氨酸剥夺导致 HDAC6 保留在细胞核中并诱导 DNA 损伤。从机制上讲，核定位的 HDAC6 结合并去乙酰化 10-11 易位 2 （TET2） 以启动活性 DNA 去甲基化，从而通过胸腺嘧啶 DNA 糖基化酶驱动的切除促进 DNA 损伤。饮食缬氨酸限制抑制异种移植物和患者来源的异种移植物模型中的肿瘤生长，并增强 PARP 抑制剂的治疗效果。总的来说，我们的研究将人类 HDAC6 确定为一种缬氨酸传感器，可介导活性 DNA 去甲基化和 DNA 损伤以响应缬氨酸剥夺，并强调了饮食缬氨酸限制治疗癌症的潜力。