Kaempferol belongs to the flavonoid family and has been used in traditional folk medicine. Here, we investigated the antitumor effects of kaempferol on cell cycle arrest and autophagic cell death in SK-HEP-1 human hepatic cancer cells. Kaempferol decreased cell viability as determined by MTT assays and induced a G2/M phase cell cycle arrest in a concentration-dependent manner. Kaempferol did not induce DNA fragmentation, apoptotic bodies or caspase-3 activity in SK-HEP-1 cells as determined by DNA gel electrophoresis, DAPI staining and caspase-3 activity assays, respectively. In contrast, kaempferol is involved in the autophagic process. Double-membrane vacuoles, lysosomal compartments, acidic vesicular organelles and cleavage of microtubule-associated protein 1 light chain 3 (LC3) were observed by transmission electron microscopy, LysoΤracker red staining, GFP-fluorescent LC3 assays and acridine orange staining, respectively. In SK-HEP-1 cells, kaempferol increased the protein levels of p-AMPK, LC3-II, Atg 5, Atg 7, Atg 12 and beclin 1 as well as inhibited the protein levels of CDK1, cyclin B, p-AKT and p-mTOR. Taken together, CDK1/cyclin B expression and the AMPK and AKT signaling pathways contributed to kaempferol-induced G2/M cell cycle arrest and autophagic cell death in SK-HEP-1 human hepatic cancer cells. These results suggest that kaempferol may be useful for long-term cancer prevention.

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Current anti-epidermal growth factor receptor (EGFR) therapy for oral cancer does not provide satisfactory efficacy due to drug resistance or reduced EGFR level. As an alternative candidate target for therapy, here we identified an oncogene, ROS1, as an important driver for oral squamous cell carcinoma (OSCC) metastasis. Among tumors from 188 oral cancer patients, upregulated ROS1 expression strongly correlated with metastasis to lung and lymph nodes. Mechanistic studies uncover that the activated ROS1 results from highly expressed ROS1 gene instead of gene rearrangement, a phenomenon distinct from other cancers. Our data further reveal a novel mechanism that reduced histone methyltransferase EZH2 leads to a lower trimethylation of histone H3 lysine 27 suppressive modification, relaxes chromatin, and promotes the accessibility of the transcription factor STAT1 to the enhancer and the intron regions of ROS1 target genes, CXCL1 and GLI1, for upregulating their expressions. Down-regulation of ROS1 in highly invasive OSCC cells, nevertheless, reduces cell proliferation and inhibits metastasis to lung in the tail-vein injection and the oral cavity xenograft models. Our findings highlight ROS1 as a candidate biomarker and therapeutic target for OSCC. Finally, we demonstrate that co-targeting of ROS1 and EGFR could potentially offer an effective oral cancer therapy.