Multiple roles of HOX proteins in Metastasis: Let me count the ways
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Multiple roles of HOX proteins in Metastasis: Let me count the ways Joy Jonkers 1 & Priya Pai 1 & Saraswati Sukumar 1
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Knowledge of the role of HOX proteins in cancer has been steadily accumulating in the last 25 years. They are encoded by 39 HOX genes arranged in 4 distinct clusters, and have unique and redundant function in all types of cancers. Many HOX genes behave as oncogenic transcriptional factors regulating multiple pathways that are critical to malignant progression in a variety of tumors. Some HOX proteins have dual roles that are tumor-site specific, displaying both oncogenic and tumor suppressor function. The focus of this review is on how HOX proteins contribute to growth or suppression of metastasis. The review will cover HOX protein function in the critical aspects of epithelial-mesenchymal transition, in cancer stem cell sustenance and in therapy resistance, manifested as distant metastasis. The emerging role of adiposity in both initiation and progression of metastasis is described. Defining the role of HOX genes in the metastatic process has identified candidates for targeted cancer therapies that may combat the metastatic process. We will discuss potential therapeutic opportunities, particularly in pathways influenced by HOX proteins. Keywords HOX . Metastasis . EMT . Obesity . Stem cells . Therapy . Cancer . Transcription factor . Migration . Invasion . Differentiation
1 Introduction The highly conserved family of HOX proteins performs as the master architects of the adult form, providing direction in both location and timing of expression of genes necessary for proper body patterning. In mammals, there are 39 HOX genes arranged in four clusters A, B, C, D of 9-11 genes on chromosomes 7, 17, 12, and 2 [1]. HOX proteins are transcription factors governing or fine-tuning the expression of large sets of regulatory and effector genes. Their action occurs at a particular place and at a particular time during embryo patterning, organ development, and cell differentiation during embryogenesis. These events lead cells to coordinately associate, migrate, or differentiate at defined locations [2]. While their role in embryonic development was firmly established, a major shift in thinking occurred about 35 years ago brought about by the realization that HOX proteins are important for hematopoiesis throughout life [3, 4]. Soon thereafter was the
* Saraswati Sukumar [email protected] 1
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1-143, Baltimore, MD 21231, USA
seminal discovery that dysregulated HOX genes are associated with leukemia, both as chimeric partners in fusion genes and when overexpressed as the wild type [5, 6]. These findings firmly planted the seed for further research on the role of HOX genes in the genesis and progression of both liquid and solid neoplasms. Most often, HOX proteins are overexpressed in huma
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