The metabolic reprogramming of aerobic glycolysis contributes to tumorigenesis. High plasma lactate is a critical regulator in the development of many human malignancies; however, the underlying molecular mechanisms of cancer progression in response to lactate (LA) remain elusive. Here, we show that the reduction of Yin-Yang 1 (YY1) expression correlated with high LA commonly occurs in various cancer cell types, including B-lymphoma and cervical cancer. Mechanistically, LA induces YY1 nuclear export and degradation via HSP70-mediated autophagy adjacent to mitochondria in a histidine (His)-rich LA-responsive (LAR) motif-dependent manner. The mutation of the LAR motif blocks LA-mediated YY1 cytoplasmic accumulation and in turn enhances cell apoptosis. Furthermore, low expression of YY1 promotes colony formation, invasion, angiogenesis, and growth of cancer cells in response to LA in vitro and in vivo using a murine xenograft model. Taken together, our findings reveal a key LAR element and may serve as therapeutic target for intervening cancer progression.

Implications: We have shown that lactate can induce YY1 degradation via its His-rich LAR motif and low expression of YY1 promotes cancer cell progression in response to lactate, leading to better prediction of YY1 targeting therapy.

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