Fane Mitchell, Harris Lachlan, Smith Aaron G, Piper Michael
The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.
School of Biomedical Sciences, Institute of Health and Biomedical Innovation at the Translational Research Institute, Queensland University of Technology, Woolloongabba, QLD, Australia.
Int J Cancer. 2017 Jun 15;140(12):2634-2641. doi: 10.1002/ijc.30603. Epub 2017 Feb 8.
Tumour heterogeneity poses a distinct obstacle to therapeutic intervention. While the initiation of tumours across various physiological systems is frequently associated with signature mutations in genes that drive proliferation and bypass senescence, increasing evidence suggests that tumour progression and clonal diversity is driven at an epigenetic level. The tumour microenvironment plays a key role in driving diversity as cells adapt to demands imposed during tumour growth, and is thought to drive certain subpopulations back to a stem cell-like state. This stem cell-like phenotype primes tumour cells to react to external cues via the use of developmental pathways that facilitate changes in proliferation, migration and invasion. Because the dynamism of this stem cell-like state requires constant chromatin remodelling and rapid alterations at regulatory elements, it is of great therapeutic interest to identify the cell-intrinsic factors that confer these epigenetic changes that drive tumour progression. The nuclear factor one (NFI) family are transcription factors that play an important role in the development of many mammalian organ systems. While all four family members have been shown to act as either oncogenes or tumour suppressors across various cancer models, evidence has emerged implicating them as key epigenetic regulators during development and within tumours. Notably, NFIs have also been shown to regulate chromatin accessibility at distal regulatory elements that drive tumour cell dissemination and metastasis. Here we summarize the role of the NFIs in cancer, focusing largely on the potential mechanisms associated with chromatin remodelling and epigenetic modulation of gene expression.
肿瘤异质性对治疗干预构成了独特的障碍。虽然在各种生理系统中肿瘤的起始通常与驱动增殖和绕过衰老的基因中的标志性突变相关，但越来越多的证据表明肿瘤进展和克隆多样性是在表观遗传水平上驱动的。肿瘤微环境在驱动多样性方面起着关键作用，因为细胞适应肿瘤生长过程中施加的需求，并被认为将某些亚群驱动回干细胞样状态。这种干细胞样表型使肿瘤细胞通过利用促进增殖、迁移和侵袭变化的发育途径对外部信号作出反应。由于这种干细胞样状态的动态性需要持续的染色质重塑和调控元件的快速改变，因此确定赋予这些驱动肿瘤进展的表观遗传变化的细胞内在因素具有极大的治疗意义。核因子一（NFI）家族是在许多哺乳动物器官系统发育中起重要作用的转录因子。虽然在各种癌症模型中已表明所有四个家族成员都可作为癌基因或肿瘤抑制因子发挥作用，但有证据表明它们在发育过程中和肿瘤内是关键的表观遗传调节因子。值得注意的是，NFI还被证明可调节驱动肿瘤细胞播散和转移的远端调控元件处的染色质可及性。在这里，我们总结了NFI在癌症中的作用，主要关注与染色质重塑和基因表达的表观遗传调控相关的潜在机制。
