University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655, United States.
Semin Cancer Biol. 2013 Apr;23(2):99-108. doi: 10.1016/j.semcancer.2012.06.008. Epub 2012 Jun 18.
In recent years it has been recognized that the development of cancer involves a series of not only genetic but epigenetic changes across the genome. At the same time, connections between epigenetic regulation, chromatin packaging, and overall nuclear architecture are increasingly appreciated. The cell-type specific organization of heterochromatin, established upon cell differentiation, is responsible for maintaining much of the genome in a repressed state, within a highly compartmentalized nucleus. This review focuses on recent evidence that in cancer the normal packaging and higher organization of heterochromatin is often compromised. Gross changes in nuclear morphology have long been a criterion for pathologic diagnosis of many cancers, but the specific nuclear components impacted, the mechanisms involved, and the implications for cancer progression have barely begun to emerge. We discuss recent findings regarding distinct heterochromatin types, including the inactive X chromosome, constitutive heterochromatin of peri/centric satellites, and the peripheral heterochromatic compartment (PHC). A theme developed here is that the higher-order organization of satellites and the peripheral heterochromatic compartment may be tightly linked, and that compromise of this organization may promote broad epigenomic imbalance in cancer. Recent studies into the potential role(s) of the breast cancer tumor suppressor, BRCA1, in maintaining heterochromatin will be highlighted. Many questions remain about this new area of cancer epigenetics, which is likely more important in cancer development and progression than widely appreciated. We propose that broad, stochastic compromise in heterochromatin maintenance would create a diversity of expression profiles, and thus a rich opportunity for one or more cells to emerge with a selective growth advantage and potential for neoplasia.
近年来，人们已经认识到癌症的发展不仅涉及基因组范围内的一系列遗传变化，还涉及表观遗传变化。与此同时，人们越来越认识到表观遗传调控、染色质包装和整体核结构之间的联系。异染色质的细胞类型特异性组织，在细胞分化后建立，负责在高度分隔的核内将大部分基因组维持在抑制状态。这篇综述重点介绍了最近的证据，表明在癌症中，正常的异染色质包装和高级组织通常会受到影响。核形态的巨大变化长期以来一直是许多癌症病理诊断的标准，但受影响的具体核成分、涉及的机制以及对癌症进展的影响才刚刚开始显现。我们讨论了最近关于不同异染色质类型的发现，包括失活 X 染色体、周边卫星的组成型异染色质和外周异染色质区室（PHC）。这里发展的一个主题是，卫星和外周异染色质区室的高级组织可能紧密相连，这种组织的破坏可能会促进癌症中广泛的表观基因组失衡。我们将重点介绍最近关于乳腺癌肿瘤抑制因子 BRCA1 在维持异染色质方面的潜在作用的研究。关于这个癌症表观遗传学的新领域仍然存在许多问题，它在癌症的发展和进展中可能比人们普遍认识的更为重要。我们提出，异染色质维持的广泛、随机破坏将产生多种表达谱，从而为一个或多个细胞提供具有选择性生长优势和潜在肿瘤形成的机会。
