title: MED27 promotes melanoma growth by targeting AKT/MAPK and NF-κB/iNOS signaling pathways.
abstract: The inhibitors of BRAF and MEK targeting MAPK signaling pathway provide a comparatively effective therapeutic strategy for melanoma caused by BRAF mutation. However, melanoma, especially metastatic melanoma, has become one of the most threatening malignancies. Thus, the identification of exact molecular mechanisms and the key components involved in such mechanisms is urgently needed in order to provide new therapeutic options for patients with melanoma. Here, we identified MED27 as a potential melanoma target and explored its role and the associated molecular mechanism involved in melanoma progression. MED27 was found to be highly expressed in melanoma cells and tumor tissues. Its silencing led to melanoma cell proliferation inhibition, cell cycle arrest and apoptosis induction accompanied by the inactivation of PI3K/AKT and MAPK/ERK signaling and the activation of Bax/Cyto-C/Caspase-dependent apoptotic pathway. In addition, silencing of MED27 led to the decrease of iNOS expression through inhibiting the activation of a serial of upstream key proteins of NF-κB signaling pathway and the translocation of p50/p65 from cytoplasm to nucleus. MED27 was also found to be able to interact with NF-κB and p300 and to be acetylated by p300. Furthermore, the results in a xenograft tumor model indicated that melanoma progression was effectively suppressed by MED27 knockdown accompanied by the down-regulation of p-AKT, p-ERK, p-MEK1/2, MMP-9, Bcl-2 and iNOS expressions in the tumor tissues. Taken together, our study not only demonstrated the new function of MED27 as an oncogenic protein and the associated molecular mechanisms involved in melanoma progression, but also provided a possibility for the development of MED27 as a new anticancer target in melanoma therapy.
authors.affiliation: Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Ranran
authors.initials: R
authors.lastname: Tang
authors.affiliation: Department of Thyroid & Breast Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Xu
authors.affiliation: Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Yang
authors.affiliation: Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Wendan
authors.initials: W
authors.lastname: Yu
authors.affiliation: Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Hou
authors.affiliation: Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xuan
authors.affiliation: Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Shilei
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China; State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
authors.affiliation: Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China. Electronic address: wei1015@dmu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China. Electronic address: liman126126@163.com.
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China; State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China. Electronic address: dengwg@sysucc.org.cn.
authors.forename: Wuguo
authors.initials: W
authors.lastname: Deng
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D056892:Mediator Complex / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014162:Transfection; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; C492154:MED27 protein, human; D056892:Mediator Complex; D016328:NF-kappa B; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases
keywords: AKT; MAPK; MED27; Melanoma; NF-κB; iNOS