Subcellular Trafficking of Oncoprotein FOXK1 Reverses Insulin Resistance-induced Circadian Disruption and Promotes Sensitivity of Metformin in Tumor Therapy
The pathophysiological function of the FOXK family-member FOXK1 remains to be explored. Although tumors classically induce abnormalities in the insulin pathway, clinical trials have failed to establish insulin receptors as potential targets for tumor therapy. Metformin, so far has been identified as an effective treatment in several clinical oncology trials; however, metformin may fail to benefit all patients, and some even suffer from many side effects and drug resistance. Herein, we report that FOXK1 expression correlates with the sensitivity to metformin treatment in a variety of tumors. FOXK1 translocates into the nucleus in response to insulin stimulation and recruits multiple class I HDAC-containing complexes that regulate the expression of genes, such as PER2 and OGT, known to be critically involved in circadian rhythm and insulin resistance. Furthermore, high insulin levels associated with cancer could disturb the subcellular localization and epigenetic regulatory functions of FOXK1. Glycosylation modifications stabilize FOXK1 in the nucleus. Elevated nuclear FOXK1 competes with CLOCK for binding with BMAL1, leading to the deregulation of circadian rhythm, which, in turn, enhanced tumor cell proliferation in vitro and promoted tumor development in vivo. Correspondingly, elevated expression of nuclear FOXK1 was observed during tumor progression and was associated with a poor prognosis. Interestingly, both in vitro and in vivo experiments confirmed that cells with high FOXK1 expression were highly responsive to metformin stimulation. Collectively, these findings revealed that nuclear FOXK1 promotes tumorigenesis by disrupting circadian rhythm under insulin resistance, and its expression may serve as a potential indicator for the adjuvant treatment of tumors using metformin. Overall design: Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for FOXK1 in MCF-7 cells.