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.

The asymmetric allylic alkylation (AAA), which features employing active allylic substrates, has historical significance in organic synthesis. The allylic C−H alkylation is principally more atom-and step-economic than the classical allylic functionalizations and thus can be considered a transformative variant. However, asymmetric allylic C−H alkylation reactions are still scarce and yet underdeveloped. Herein, we have found that Z/E-and regioselectivities in the Pd-catalyzed asymmetric allylic C−H alkylation of 1,4-dienes are highly dependent on the type of nucleophiles. A highly stereoselective allylic C−H alkylation of 1,4-dienes with azlactones has been established by palladium-chiral phosphoramidite catalysis. The protocol proceeds under mild conditions and can accommodate a wide scope of substrates, delivering structurally divergent α,αdisubstituted α-amino acid surrogates in high yields and excellent levels of diastereo-, Z/E-, regio-, and enantioselectivities. Notably, this method provides key chiral intermediates for an efficient synthesis of lepadiformine marine alkaloids. Experimental and computational studies on the reaction mechanism suggest a novel concerted proton and two-electron transfer process for the allylic C−H cleavage and reveal that the Z/E-and regioselectivities are governed by the geometry and coordination pattern of nucleophiles.

Incorporation of microbiome data has recently become important for prevention, diagnosis, and treatment of colorectal cancer, and several species of bacteria were shown to be associated with carcinogenesis. However, the role of commensal fungi in colon cancer remains poorly understood. Here, we report that mice lacking the c-type lectin Dectin-3 (Dectin-3 À/À ) show increased tumorigenesis and Candida albicans burden upon chemical induction. Elevated C. albicans load triggered glycolysis in macrophages and interleukin-7 (IL-7) secretion. IL-7 induced IL-22 production in RORct + (group 3) innate lymphoid cells (ILC3s) via aryl hydrocarbon receptor and STAT3. Consistently, IL-22 frequency in tumor tissues of colon cancer patients positively correlated with fungal burden, indicating the relevance of this regulatory axis in human disease. These results establish a C. albicans-driven crosstalk between macrophages and innate lymphoid cells in the intestine and expand our understanding on how commensal mycobiota regulate host immunity and promote tumorigenesis.

No abstract