Androgen receptor (AR) is a hormone-regulated transcription factor that mediates a wide array of biological processes including sexual differentiation, spermatogenesis, and prostate cancer progression. The transcriptional activity of AR and other members of the nuclear receptor superfamily are modulated by coregulatory proteins. In this study, we have investigated the regulation of AR transcriptional activity by the silencing mediator for retinoid and thyroid hormone receptors (SMRT). We found that AR possesses an intrinsic transcriptional repression activity, and AR interacts directly with SMRT. One interacting surface on AR is mapped to the ligand-binding domain, and the presence of a DNA binding/hinge region enhances this interaction. The binding surface on SMRT is mapped to the C-terminal ID2 region, and mutation in the ID2 corepressor motif inhibits the interaction. Overexpression of SMRT inhibits dihydrotestosterone-dependent transactivation by AR and further suppresses the antiandrogen flutamide-mediated inhibition of AR activity. We provide evidence to suggest that the mechanisms of SMRT-mediated inhibition of AR activity involves inhibition of AR N/C interaction and competition with the p160 coactivator. Our data establish a significant role of SMRT in modulating AR transcriptional activity. Androgen receptor (AR)1 is a member of the nuclear receptor (NR) superfamily that mediates the biological effects of the male sex hormone androgens in a wide range of physiological processes, including sexual differentiation and maturation, spermatogenesis, and gonadotropin regulation (1). AR is also involved in the development and progression of prostate cancer, which is one of the most frequently diagnosed cancers in males. Indeed, somatic mutations of the AR gene have been found in prostate tumors, which may contribute to androgenindependent growth of the cancer cell (2). Treatment with antiandrogens can partially or completely arrest prostate cancer cell proliferation. Similar to other steroid receptors the unliganded AR is held in an inactive conformation by association with heat shock proteins in the cytoplasm. The heat shock protein complex assists in maintaining an AR conformation that is active to ligand binding. Upon ligand binding, the heat shock protein complex dissociates from the receptor (3), allowing AR to homodimerize and translocate to the nucleus, where it recognizes and binds specific promoter elements to activate gene expression (4).Like other members of the NR superfamily, AR contains an N-terminal AF-1 transactivation domain (or A/B domain), a centrally located DNA-binding domain (DBD or C domain), a hinge region (or D domain), and a ligand-binding domain (LBD or E domain). The E domain is also involved in receptor dimerization and contains ligand-dependent AF-2 function. The A/B domain is the most variable among NRs, and in the case of AR, it contains two separate transactivation domains that are required for full ligand-inducible transcription activity (5, 6). The A/B region also contains a...

Background:Emerging evidence has demonstrated that lysine-specific demethylase 1 (LSD1) has an important role in many pathological processes of cancer cells, such as carcinogenesis, proliferation and metastasis. In this study, we characterised the role and molecular mechanisms of LSD1 in proliferation and metastasis of colon cancer.Methods:We evaluated the correlation of LSD1, CDH-1 and CDH-2 with invasiveness of colon cancer cells, and investigated the roles of LSD1 in proliferation, invasion and apoptosis of colon cancer cells. We further investigated the mechanisms of LSD1-mediated metastasis of colon cancer.Results:Lysine-specific demethylase 1 was upregulated in colon cancer tissues, and the high LSD1 expression was significantly associated with tumour-node-metastasis (TNM) stages and distant metastasis. Functionally, inhibition of LSD1 impaired proliferation and invasiveness, and induced apoptosis of colon cancer cells in vitro. The LSD1 physically interacted with the promoter of CDH-1 and decreased dimethyl histone H3 lysine 4 (H3K4) at this region, downregulated CDH-1 expression, and consequently contributed to colon cancer metastasis.Conclusion:Lysine-specific demethylase 1 downregulates the expression of CDH-1 by epigenetic modification, and consequently promotes metastasis of colon cancer cells. The LSD1 antagonists might be a useful strategy to suppress metastasis of colon cancer.

Increasing evidence reveals that aberrant expression of microRNA contributes to the development and progression of colon cancer, but the roles of microRNA-506 (miR-506) in colon cancer remain elusive. Here, we demonstrated that miR-506 was down-regulated in colon cancer tissue and cells and that miR-506 expression was inversely correlated with EZH2 expression, tumor size, lymph node invasion, TNM stage and metastasis. A high level of miR-506 identified patients with a favorable prognosis. In vitro and in vivo experiments confirmed that miR-506 inhibits the proliferation and metastasis of colon cancer, and a luciferase reporter assay confirmed that EZH2 is a direct and functional target of miR-506 via the 3′UTR of EZH2. The restoration of EZH2 expression partially reversed the proliferation and invasion of miR-506-overexpressing colon cancer cells. Moreover, we confirmed that the miR-506-EZH2 axis inhibits proliferation and metastasis by activating/suppressing specific downstream tumor-associated genes and the Wnt/β-catenin signaling pathway. Taking together, our study sheds light on the role of miR-506 as a suppressor for tumor growth and metastasis and raises the intriguing possibility that miR-506 may serve as a new potential marker for monitoring and treating colon cancer.

The location of rectal GIST impacts the choice of resection type. Most patients with tumors within 5 cm of the anal verge can be treated with local excision. Positive resection margin is the independent hazard factor for poorer survival. Peri-operative Imatinib therapy is associated with a prolonged DFS in patients with intermediate and high-risk tumors.

Compared with ODG, LADG with D2 dissection has the advantages of minimal invasion, faster recovery, and fewer complications, and it can achieve the same degree of radicality and short-term prognosis as ODG. The drawbacks are that the operating time is slightly longer and long-term prognosis is not clear.