title: Nuclear matrix protein SMAR1 represses c-Fos-mediated HPV18 E6 transcription through alteration of chromatin histone deacetylation.
abstract: Matrix attachment region (MAR)-binding proteins have been implicated in the transcriptional regulation of host as well as viral genes, but their precise role in HPV-infected cervical cancer remains unclear. Here we show that HPV18 promoter contains consensus MAR element in the LCR and E6 sequences where SMAR1 binds and reinforces HPV18 E6 transcriptional silencing. In fact, curcumin-induced up-regulation of SMAR1 ensures recruitment of SMAR1-HDAC1 repressor complex at the LCR and E6 MAR sequences, thereby decreasing histone acetylation at H3K9 and H3K18, leading to reorientation of the chromatin. As a consequence, c-Fos binding at the putative AP-1 sites on E6 promoter is inhibited. E6 depletion interrupts degradation of E6-mediated p53 and lysine acetyl transferase, Tip60. Tip60, in turn, acetylates p53, thereby restoring p53-mediated transactivation of proapoptotic genes to ensure apoptosis. This hitherto unexplained function of SMAR1 signifies the potential of this unique scaffold matrix-associated region-binding protein as a critical regulator of E6-mediated anti-apoptotic network in HPV18-infected cervical adenocarcinoma. These results also justify the candidature of curcumin for the treatment of HPV18-infected cervical carcinoma.
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P1/12, Calcutta Improvement Trust Scheme VIIM, Kolkata 700054, West Bengal, India.
authors.forename: Samik
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P1/12, Calcutta Improvement Trust Scheme VIIM, Kolkata 700054, West Bengal, India.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Das
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P1/12, Calcutta Improvement Trust Scheme VIIM, Kolkata 700054, West Bengal, India.
authors.forename: Shilpi
authors.initials: S
authors.lastname: Saha
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P1/12, Calcutta Improvement Trust Scheme VIIM, Kolkata 700054, West Bengal, India.
authors.forename: Minakshi
authors.initials: M
authors.lastname: Mazumdar
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P1/12, Calcutta Improvement Trust Scheme VIIM, Kolkata 700054, West Bengal, India.
authors.forename: Argha
authors.initials: A
authors.lastname: Manna
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P1/12, Calcutta Improvement Trust Scheme VIIM, Kolkata 700054, West Bengal, India.
authors.forename: Sreeparna
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P1/12, Calcutta Improvement Trust Scheme VIIM, Kolkata 700054, West Bengal, India.
authors.forename: Shravanti
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P1/12, Calcutta Improvement Trust Scheme VIIM, Kolkata 700054, West Bengal, India.
authors.forename: Poulami
authors.initials: P
authors.lastname: Khan
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P1/12, Calcutta Improvement Trust Scheme VIIM, Kolkata 700054, West Bengal, India.
authors.forename: Arghya
authors.initials: A
authors.lastname: Adhikary
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P1/12, Calcutta Improvement Trust Scheme VIIM, Kolkata 700054, West Bengal, India.
authors.forename: Suchismita
authors.initials: S
authors.lastname: Mohanty
authors.affiliation: the National Centre for Cell Science, Pune University Campus, Ganeshkhind, Pune 411007, Maharashtra, India, and.
authors.forename: Samit
authors.initials: S
authors.lastname: Chattopadhyay
authors.affiliation: the Department of Gynecology & Obstetrics, Institute of Post-Graduate Medical Education and Research (IPGMER), Seth Sukhlal Karnani Memorial (SSKM) Hospital, Kolkata 700020, West Bengal, India.
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Biswas
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P1/12, Calcutta Improvement Trust Scheme VIIM, Kolkata 700054, West Bengal, India.
authors.forename: Gaurisankar
authors.initials: G
authors.lastname: Sa
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P1/12, Calcutta Improvement Trust Scheme VIIM, Kolkata 700054, West Bengal, India, tanya@jcbose.ac.in.
authors.forename: Tanya
authors.initials: T
authors.lastname: Das
mesh_terms: D000107:Acetylation; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C417914:BANP protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; D006657:Histones; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1
keywords: Cancer Prevention; FBJ Murine Osteosarcoma Viral Oncogene Homolog (Fos); Histone Deacetylase (HDAC); Papillomavirus; Transcription Repressor