title: Cooperatively transcriptional and epigenetic regulation of sonic hedgehog overexpression drives malignant potential of breast cancer.
abstract: Sonic hedgehog (Shh), a ligand of Hedgehog signaling pathway, is considered an important oncogene and an exciting potential therapeutic target in several cancers. Comprehensive understanding of the regulation mechanism of Shh in cancer cells is necessary to find an effective approach to selectively block its tumorigenic function. We and others previously demonstrated that nuclear factor-kappa B (NF-κB) activation and promoter hypomethylation contributed to the overexpression of Shh. However, the relationship between transcriptional and epigenetic regulation of Shh, and their roles in the malignant phenotype of cancer cells are still not clearly elucidated. In the present study, our data showed that the level of Shh was higher in breast cancer tissues with positive NF-κB nuclear staining and promoter hypomethylation. In addition, survival analysis revealed that Shh overexpression, but not hypomethylation and NF-κB nuclear staining, was a poor prognosis indicator for breast cancers. Moreover, in vitro data demonstrated that both NF-κB activation and hypomethylation in promoter region were positively associated with the overexpression of Shh. Mechanistically, the hypomethylation in Shh promoter could facilitate NF-κB binding to its site, and subsequently cooperate to induce transcription of Shh. Furthermore, the biological function data indicated that overexpressed Shh enhanced the self-renewal capacity and migration ability of breast cancer cells, which could be augmented by promoter demethylation and NF-κB activation. Overall, our findings reveal multiple and cooperative mechanisms of Shh upregulation in cancer cells, and the roles of Shh in tumor malignant behavior, thus suggesting a new strategy for therapeutic interventions to reduce Shh in tumors and improve patients' prognosis.
authors.affiliation: Department of Pharmacology, College of Life Science and Biopharmaceutical of Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Zhao-Heng
authors.initials: ZH
authors.lastname: Duan
authors.affiliation: Department of Pharmacology, College of Life Science and Biopharmaceutical of Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Hao-Chuan
authors.initials: HC
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, College of Life Science and Biopharmaceutical of Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, College of Life Science and Biopharmaceutical of Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Xiao-Xin
authors.initials: XX
authors.lastname: Ji
authors.affiliation: Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, China.
authors.forename: Min
authors.initials: M
authors.lastname: Song
authors.affiliation: Center for Neuroscience, Medical College of Shantou University, Shantou, China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, College of Life Science and Biopharmaceutical of Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D053823:Hedgehog Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000502:physiology*; D014162:Transfection; D015854:Up-Regulation
chemical_list: D053823:Hedgehog Proteins; C509239:SHH protein, human
keywords: Breast cancer; NF-κB; Sonic hedgehog; hypomethylation; transcriptional regulation