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  • Sudhir Krishnaa br a National Centre

    2020-03-17

    Sudhir Krishnaa,
    a National Centre for Biological Sciences, Tata Institute of Fundamental Research, GKVK-UAS, Bangalore 560065, Karnataka, India b Department of Pathology, Kidwai Cancer Institute, Bangalore, India c The Babraham Institute, Cambridge, UK d School of Biological Sciences, University of Essex, Colchester, UK
    Keywords:
    Cervical cancer
    Intratumoural heterogeneity
    Cell migration
    Chromatin
    Genomics 
    Metastatic progression is a major cause of mortality in cervical cancers, but factors regulating migratory and pre-metastatic cell populations remain poorly understood. Here, we sought to assess whether a SUV39H1-low chromatin state promotes migratory cell populations in cervical cancers, using meta-analysis of data from The Cancer Genome Atlas (TCGA), immunohistochemistry, genomics and functional assays. Cervical cancer N-octanoyl-L-Homoserine lactone sorted based on migratory ability in vitro have low levels of SUV39H1 protein, and SUV39H1 knockdown in vitro enhanced cervical cancer cell migration. Further, TCGA SUV39H1-low tumours correlated with poor clinical outcomes and showed gene expression signatures of cell migration. SUV39H1 expression was examined within biopsies, and SUV39H1low cells within tumours also demonstrated migratory features. Next, to understand genome scale transcriptional and chromatin changes in migratory populations, cell populations sorted based on migration in vitro were examined using RNA-Seq, along with ChIP-Seq for H3K9me3, the histone mark associated with SUV39H1. Migrated populations showed SUV39H1-linked migratory gene expression signatures, along with broad depletion of H3K9me3 across gene promoters. We show for the first time that a SUV39H1-low chromatin state associates with, and promotes, migratory populations in cervical cancers. Our results posit SUV39H1-low cells as key populations for prognosis estimation and as targets for novel therapies.
    1. Introduction
    Despite significant advances in vaccination and screening, cervical cancer represents one of the most common cancers in women in the developing world. While considerable insights have emerged on early stages of cervical cancer progression using in vitro and mouse models [1], advanced progression stages, including metastasis, are still poorly understood - in part due to due to extensive heterogeneity within and across human tumours. In particular, the emergence of migratory sub-populations within tumours represents a rate N-octanoyl-L-Homoserine lactone limiting step during multiphase process of metastasis. We have previously reported that one such population in cervical cancer progression, marked by CEACAM/ CD66, shows enhanced tumorigenicity, migration, and associations with metastasis [2–4]. However, it is poorly understood what broad mechanisms regulate such migratory populations during advanced progression, and how they would allow fate plasticity - the switch
    Corresponding author.
    E-mail address: [email protected] (S. Krishna). 
    between proliferative and migratory states, allowing the formation of macroscopic distant metastases.
    One possible mechanism that could regulate such plasticity during migration and metastasis is heterochromatin regulation, through me-tastable changes in chromatin conformation. We have previously re-ported that CD66-enriched spheroid cultures show differential expres-sion of several chromatin regulators, including a depletion of heterochromatin regulator SUV39H1 [2,3]. SUV39H1 effects tran-scriptional silencing through H3K9 trimethylation (H3K9me3), and SUV39H1-regulated heterochromatin has previously been demon-strated to play a barrier to cell fate transitions during iPSC repro-gramming and T-cell lineage commitment [5–9]. In this study, we ex-amined whether a SUV39H1-low chromatin state is associated with, and regulates, migratory populations in cervical carcinomas. Metastatic transitions in cancers have frequently studied using treatment of cells with growth factors in vitro to induce an Epithelial to