title: Tumor-suppressive p53 Signaling Empowers Metastatic Inhibitor KLF17-dependent Transcription to Overcome Tumorigenesis in Non-small Cell Lung Cancer.
abstract: Metastasis, which is controlled by concerted action of multiple genes, is a complex process and is an important cause of cancer death. Krüppel-like factor 17 (KLF17) is a negative regulator of metastasis and epithelial-mesenchymal transition (EMT) during cancer progression. However, the underlying molecular mechanism and biological relevance of KLF17 in cancer cells are poorly understood. Here, we show that tumor suppressor protein p53 plays an integral role to induce KLF17 expression in non-small cell lung cancer (NSCLC). p53 is recruited to the KLF17 promoter and results in the formation of p53-DNA complex. p53 enhances binding of p300 and favors histone acetylation on the KLF17 promoter. Mechanistically, p53 physically interacts with KLF17 and thereby enhances the anti-metastatic function of KLF17. p53 empowers KLF17-mediated EMT genes transcription via enhancing physical association of KLF17 with target gene promoters. Nutlin-3 recruits KLF17 to EMT target gene promoters and results in the formation of KLF17-DNA complex via a p53-dependent pathway. p53 depletion abrogates DNA binding affinity of KLF17 to EMT target gene promoters. KLF17 is critical for p53 cellular activities in NSCLC. Importantly, KLF17 enhances p53 transcription to generate a novel positive feedback loop. KLF17 depletion accelerates lung cancer cell growth in response to chemotherapy. Mechanistically, we found that KLF17 increases the expression of tumor suppressor genes p53, p21, and pRB. Functionally, KLF17 required p53 to suppress cancer cell invasion and migration in NSCLC. In conclusion, our study highlights a novel insight into the anti-EMT effect of KLF17 via a p53-dependent pathway in NSCLC, and KLF17 may be a new therapeutic target in NSCLC with p53 status.
authors.affiliation: From the Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China, the Department of Biotechnology, Abdul Wali Khan University, Mardan 23200, Pakistan amjad_486@yahoo.com.
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.affiliation: From the Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China, the Department of Biotechnology, Abdul Wali Khan University, Mardan 23200, Pakistan.
authors.forename: Muhammad Zeeshan
authors.initials: MZ
authors.lastname: Bhatti
authors.affiliation: From the Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Abdus Saboor
authors.initials: AS
authors.lastname: Shah
authors.affiliation: the Institute of Research and Development, Duy Tan University, K7/25 Quang Trung, Danang 59000, Vietnam.
authors.forename: Hong-Quan
authors.initials: HQ
authors.lastname: Duong
authors.affiliation: the Pharmacology Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudia Arabia.
authors.forename: Huda Mohammad
authors.initials: HM
authors.lastname: Alkreathy
authors.affiliation: the Laboratory of Enzymology and Molecular Evolution, State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China, the Department of Biotechnology, Faculty of Biological Sciences, University of Science and Technology Bannu, Khyber Pakhtunkhwa, Pakistan.
authors.forename: Shah Faisal
authors.initials: SF
authors.lastname: Mohammad
authors.affiliation: the Department of Biotechnology, Faculty of Biological Sciences, University of Science and Technology Bannu, Khyber Pakhtunkhwa, Pakistan.
authors.forename: Rahmat Ali
authors.initials: RA
authors.lastname: Khan
authors.affiliation: the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China, and the Department of Biotechnology, Abdul Wali Khan University, Mardan 23200, Pakistan ahdayazb5@awkum.edu.pk.
authors.forename: Ayaz
authors.initials: A
authors.lastname: Ahmad
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C510638:KLF17 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53
keywords: KLF17; Metastasis; chemotherapy; lung cancer; tumor suppressor p53