Impairment of the circadian clock is linked to cancer development. However, whether the circadian clock is modulated by oncogenic receptor tyrosine kinases remains unclear. Here we demonstrated that receptor tyrosine kinase activation promotes CK2-mediated CLOCK S106 phosphorylation and subsequent disassembly of the CLOCK–BMAL1 dimer and suppression of the downstream gene expression in hepatocellular carcinoma (HCC) cells. In addition, CLOCK S106 phosphorylation exposes its nuclear export signal to bind Exportin1 for nuclear exportation. Cytosolic CLOCK acetylates PRPS1/2 K29 and blocks HSC70-mediated and lysosome-dependent PRPS1/2 degradation. Stabilized PRPS1/2 promote de novo nucleotide synthesis and HCC cell proliferation and liver tumour growth. Furthermore, CLOCK S106 phosphorylation and PRPS1/2 K29 acetylation are positively correlated in human HCC specimens and with HCC poor prognosis. These findings delineate a critical mechanism by which oncogenic signalling inhibits canonical CLOCK transcriptional activity and simultaneously confers CLOCK with instrumental moonlighting functions to promote nucleotide synthesis and tumour growth.

生物钟的受损与癌症的发展有关。然而，生物钟是否由致癌受体酪氨酸激酶调节仍不清楚。在这里，我们证明受体酪氨酸激酶激活促进 CK2 介导的 CLOCK S106 磷酸化和随后的 CLOCK-BMAL1 二聚体分解，并抑制肝细胞癌 (HCC) 细胞中的下游基因表达。此外，CLOCK S106 磷酸化暴露其核输出信号以结合 Exportin1 进行核输出。细胞溶质 CLOCK 使 PRPS1/2 K29 乙酰化并阻断 HSC70 介导的和溶酶体依赖性 PRPS1/2 降解。稳定的 PRPS1/2 促进从头合成核苷酸和 HCC 细胞增殖和肝肿瘤生长。此外，CLOCK S106 磷酸化和 PRPS1/2 K29 乙酰化在人类 HCC 标本中呈正相关，并且与 HCC 不良预后相关。这些发现描述了致癌信号抑制典型 CLOCK 转录活性并同时赋予 CLOCK 工具兼职功能以促进核苷酸合成和肿瘤生长的关键机制。