RESUMEN
Inheritance of genomic information independent of the DNA sequence, the epigenetics, as well as gene transcription are profoundly shaped by serine/threonine and tyrosine signaling kinases and components of the chromatin remodeling complexes. To precisely respond to a changing external milieu, human cells efficiently translate upstream signals into post-translational modifications (PTMs) on histones and coregulators such as corepressors, coactivators, DNA-binding factors and PTM modifying enzymes. Because a protein with multiple residues for putative PTMs is expected to undergo more than one PTM in cells stimulated with growth factors, the outcome of combinational PTM codes on histones and coregulators is profoundly shaped by regulatory interplays between PTMs. The genomic functions of signaling kinases in cancer cells are manifested by the downstream effectors of cytoplasmic signaling cascades as well as translocation of the cytoplasmic signaling kinases to the nucleus. Signaling-mediated phosphorylation of histones serves as a regulatory switch for other PTMs, and connects chromatin remodeling complexes into gene transcription and gene activity. Here, we will discuss the recent advances in signaling-dependent epigenomic regulation of gene transcription using a few representative cancer-relevant serine/threonine and tyrosine kinases and their interplay with chromatin remodeling factors in cancer cells.
Asunto(s)
Epigenómica , Neoplasias/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Ensamble y Desensamble de Cromatina/genética , Regulación Neoplásica de la Expresión Génica , Histonas/genética , Humanos , Fosforilación , Procesamiento Proteico-Postraduccional/genética , Transducción de SeñalRESUMEN
Chromatin remodeling factor metastatic tumor protein 1 (MTA1), one of the most upregulated oncogene in human cancer, has an important role in gene expression, cell survival and promoting hypoxic response. Successful cancer progression is dependent on the ability of cells to utilize its survival pathways for adapting to hypoxic microenvironment. Although MTA1 is a stress-responsive gene, but whether hypoxia modulates its function and its role in engaging other core stress-responsive survival pathway(s) remains unknown. Here we have discovered that MTA1 is a novel corepressor of serum and glucocorticoid-inducible kinase 1 (SGK1). Surprisingly, this regulatory corepressive function of MTA1 is lost under hypoxia, allowing upregulation of SGK1 expression and engaging the MTA1-SGK1 axis for the benefit of the cell survival. The underlying mechanism of the noticed stimulation of SGK1 expression by hypoxia includes de-repression of SGK1 transcription because of hypoxia-triggered nucleus-to-cytoplasmic translocation of MTA1. In addition, the newly recognized cytoplasmic translocation of MTA1 was dependent on the chaperoning function of heat shock protein 90 (HSP90) and co-accompanied by the formation of MTA1, HSP90 and HIF1α complex under hypoxic condition but not under normoxic condition. Hypoxia-triggered redistribution of MTA1, SGK1 upregulation and cell survival functions were compromised by a pharmacological SGK1 inhibitor. In summary, for the first time, we report MTA1 regulation of SGK1 expression, hypoxia-dependent MTA1 translocation to the cytoplasm and de-repression of SGK1 transcription. These findings illustrate how cancer cells utilize a chromatin remodeling factor to engage a core survival pathway to support its cancerous phenotypes, and reveal new facets of MTA1-SGK1 axis by a physiologic signal in cancer progression.
Asunto(s)
Hipoxia de la Célula/fisiología , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Proteínas Inmediatas-Precoces/genética , Proteínas Inmediatas-Precoces/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Citoplasma/genética , Citoplasma/metabolismo , Femenino , Humanos , Células MCF-7 , Ratones Noqueados , Transducción de Señal , Transactivadores , TransfecciónRESUMEN
Despite a recognized role of DNA methyltransferase 3a (DNMT3a) in human cancer, the nature of its upstream regulator(s) and relationship with the master chromatin remodeling factor MTA1, continues to be poorly understood. Here, we found an inverse relationship between the levels of MTA1 and DNMT3a in human cancer and that high levels of MTA1 in combination of low DNMT3a status correlates well with poor survival of breast cancer patients. We discovered that MTA1 represses DNMT3a expression via HDAC1/YY1 transcription factor complex. Because IGFBP3 is an established target of DNMT3a, we investigated the effect of MTA1 upon IGFBP3 expression, and found a coactivator role of MTA1/c-Jun/Pol II coactivator complex upon the IGFBP3 transcription. In addition, MTA1 overexpression correlates well with low levels of DNMT3a which, in turn also correlates with a high IGFBP3 status in breast cancer patients and predicts a poor clinical outcome for breast cancer patients. These findings suggest that MTA1 could regulate the expression of IGFBP3 in both DNMT3a-dependent and -independent manner. Together findings presented here recognize an inherent role of MTA1 as a modifier of DNMT3a and IGFBP3 expression, and consequently, the role of MTA1-DNMT3a-IGFBP3 axis in breast cancer progression.
Asunto(s)
Neoplasias de la Mama/metabolismo , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Regulación Neoplásica de la Expresión Génica , Histona Desacetilasas/metabolismo , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/biosíntesis , Proteínas de Neoplasias/metabolismo , Proteínas Represoras/metabolismo , Transcripción Genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Femenino , Histona Desacetilasas/genética , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Células MCF-7 , Proteínas de Neoplasias/genética , Proteínas Represoras/genética , TransactivadoresRESUMEN
Head and neck cancers usually originate in the squamous cells that line the inner mucosal surfaces of the oral and the neck region. These cancers follow multifocal steps for progression that include risk of developing metastasis. Although therapeutics has advanced in the past decades, head and neck cancers continue to cause much morbidity and mortality. Even with the promising effect of targeted therapies, there is a need for a better evaluation of patients with head and neck cancers. Metastasis-associated tumour antigen 1 (MTA1), a chromatin modifier, is found as an integral part of nucleosome remodelling and histone deacetylation (NuRD) complex. MTA1 is a biomarker for several solid tumours, and the overexpression of which have been documented in various cancers such as breast, ovarian, colon, prostrate etc. Interestingly also, a set of head and neck cancers shows MTA1 overexpression. However, recent evidences from clinical data raise a critical question on the role of MTA1 in head and neck cancers. This calls for a detailed review to the role of MTA1 in oral cancer. This review gives a brief account on the existing biological and molecular data in the context of head and neck cancer invasion and metastasis in relation to MTA1.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de Cabeza y Cuello/genética , Histona Desacetilasas/genética , Proteínas Represoras/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello/patología , Histona Desacetilasas/biosíntesis , Humanos , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Invasividad Neoplásica/genética , Metástasis de la Neoplasia/genética , Proteínas Represoras/biosíntesis , TransactivadoresRESUMEN
Knowledge regarding cervical cancer and human papillomavirus is expanding rapidly. Inflammation subsequent to viral infection is a driving force that accelerates cancer development. The infiltrated immune cells and their secretory cytokines along with chemokines and growth factors greatly contribute the malignant traits of cervical cancer. A better understanding of the mechanisms related to inflammation and cancer progression in terms of pathogen survival, cancer development, progression, and metastasis will lead to innovative approach for treating cancer.
