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Emerging studies have revealed that O -GlcNAcylation plays pivotal roles in the tumorigenesis of colorectal cancers (CRCs). However, the underlying mechanism still remains largely unknown. Here, we demonstrated that Yin Yang 1 (YY1) was O -GlcNAcylated by O -GlcNAc transferase (OGT) and O -GlcNAcylation of YY1 could increase the protein expression by enhancing its stability. O -GlcNAcylation facilitated transformative phenotypes of CRC cell in a YY1-dependent manner. Also, O -GlcNAcylation stimulates YY1-dependent transcriptional activity. Besides, we also identified the oncoproteins, SLC22A15 and AANAT, which were regulated by YY1 directly, are responsible for the YY1 stimulated tumorigenesis. Furthermore, we identified the main putative O -GlcNAc site of YY1 at Thr236, and mutating of this site decreased the pro-tumorigenic capacities of YY1. We concluded that O -GlcNAcylation of YY1 stimulates tumorigenesis in CRC cells by targeting SLC22A15 and AANAT, suggesting that YY1 O -GlcNAcylation might be a potential effective therapeutic target for treating CRC. [ABSTRACT FROM AUTHOR]

Neurotrophin receptor-interacting melanoma antigen-encoding gene homolog (NRAGE) is generally recognized as a tumor suppressor as it induces cell apoptosis and suppresses cell metastasis. However, it has recently been reported that NRAGE is overexpressed in lung cancer, melanoma, and colon cancer, implicating a complicated role of NRAGE as we have expected. In the study, we aim to elucidate the functional roles and molecular mechanisms of NRAGE in esophageal carcinoma. We found that both NRAGE mRNA and protein were significantly overexpressed in esophageal tumor tissues. Consistently, both in vivo and in vitro analyses demonstrated that knockdown of NRAGE apparently inhibited cell growth, and cell cycle analysis further demonstrated that NRAGE knockdown cells were mainly arrested in G2M cell phase, accompanied with an apparent reduction of S phase. In the process of exploring molecular mechanisms, we found that either knockdown in vitro or knockout in vivo of NRAGE reduced proliferating cell nuclear antigen (PCNA) protein, expression of which could completely rescue the inhibited proliferation in NRAGE defective cells. Furthermore, NRAGE physically interacted with PCNA in esophageal cancer cells through DNA polymerase III subunit, and knockdown of NRAGE facilitated PCNA K48-linked polyubiquitylation, leading PCNA to the proteasome-dependent degradation and a unbiquitin specific protease USP10 was identified to be a key regulator in the process of K48 polyubiquitylation in NRAGE deleted cells. In conclusion, our study highlights a unique role of NRAGE, and implies that NRAGE is likely to be an attractive oncotarget in developing novel genetic anti-cancer therapeutic strategies for esophageal squamous cell carcinomas. [ABSTRACT FROM PUBLISHER]