Colorectal cancer pathogenesis remains incompletely understood. Here, we report that the heterochromatin protein HP1g is upregulated commonly in human colorectal cancer, where it promotes cell proliferation in vitro and in vivo. Gene-expression and promoter-binding experiments demonstrated that HP1g directly regulated CDKN1A (p21 Waf1/Cip1 ) in a manner associated with methylation of histone H3K9 on its promoter. We identified miR-30a as a tumor-suppressive microRNA that targets HP1g in vitro and in vivo to specifically suppress the growth of colorectal cancer in mouse xenograft models. MiR30a was widely downregulated in primary human colorectal cancer tissues, where its expression correlated inversely with high levels of HP1g protein. Our results identify a new miR-30a/HP1g/p21 regulatory axis controlling colorectal cancer development, which may offer prognostic and therapeutic opportunities. Cancer Res; 75(21); 4593-604. Ó2015 AACR.

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The present study assessed the antitumor effect of artesunate (ART) in vitro and in vivo, as well as its underlying mechanism of action in HCT116 colon cancer cells. An MTT assay, DAPI staining, flow cytometry, western blotting, immunohistochemistry, transmission electron microscopy and TUNEL assay were performed to study the molecular mechanism underlying the antitumor effects of ART in HCT116 colon cancer cells. ART was observed to inhibit proliferation by inducing the apoptosis of HCT116 cells both in vitro and in vivo. Flow cytometry analysis demonstrated that treatment with 2 and 4 µg/ml ART for 48 h induced early apoptosis in 22.7 and 33.8% of cells, respectively. In the xenograft tumors of BALB/c nude mice, TUNEL-positive cells increased in the ART group compared with that in the normal saline group. Furthermore,the associated mitochondrial cleaved-caspase 3, poly-ADP ribose polymerase (PARP), caspase 9 and Bcl-2-associated X protein levels increased while B-cell lymphoma-2 (Bcl-2) decreased both in the cell and animal ART-treated group. ART-treated cells also exhibited autophagy induction, as evidenced by increased protein expression levels of light chain 3 (LC3) and beclin-1, and the presence of autophagosomes. Notably, pharmacological blockade of autophagy activation using hydroxychloroquine markedly enhanced ART-induced apoptosis and increased the protein levels of cleaved caspase 3 and PARP, while decreasing the levels of LC3 and beclin-1. These findings suggested that the ART-induced autophagy may have a cytoprotective effect by suppressing apoptosis. In conclusion, ART may be a potentially clinically useful anticancer drug for human colon cancer. In addition, co-treatment with ART and an autophagy inhibitor may be an effective anticancer therapy.

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