Glucose sensing and metabolic adaptation to glucose availability in the tumor microenvironment are critical for cancer development. Here we show that HKDC1, a hexokinase highly expressed in cancer associated with poor prognosis, functions as a glucose sensor that alters its stability in response to environmental glucose. The glucose-sensing domain is located between amino acids 751-917, with Ser896 as a key residue that regulates HKDC1 stability by affecting Lys620 ubiquitination. This sensing mechanism enables cellular adaptation to glucose starvation by promoting mitochondrial fatty acid utilization. Furthermore, HKDC1 promotes tumor growth by sequestering prohibitin 2 (PHB2) to disable its suppressive effect on SP1, thus promoting the expression of pro-oncogenic molecules. Abrogation of HKDC1 by genetic knockout or by glucose depletion releases PHB2, leading to suppression of cancer cell proliferation and inhibition of tumor growth. Our study reveals a previously unrecognized role of HKDC1 in glucose sensing and metabolic adaptation, and identifies HKDC1 as a potential therapeutic target.

葡萄糖感应和对肿瘤微环境中葡萄糖可用性的代谢适应对于癌症的发展至关重要。在这里，我们表明 HKDC1 是一种在与预后不良相关的癌症中高度表达的己糖激酶，它作为葡萄糖传感器发挥作用，响应环境葡萄糖而改变其稳定性。葡萄糖感应结构域位于氨基酸 751-917 之间，其中 Ser896 是关键残基，通过影响 Lys620 泛素化来调节 HKDC1 稳定性。这种传感机制通过促进线粒体脂肪酸的利用使细胞能够适应葡萄糖饥饿。此外，HKDC1 通过隔离禁止蛋白 2 （PHB2） 以禁用其对 SP1 的抑制作用来促进肿瘤生长，从而促进促癌分子的表达。通过基因敲除或葡萄糖耗竭消除 HKDC1 会释放 PHB2，从而抑制癌细胞增殖和抑制肿瘤生长。我们的研究揭示了 HKDC1 在葡萄糖感应和代谢适应中以前未被认识的作用，并确定 HKDC1 是一个潜在的治疗靶点。