Lynch-Sutherland Chiemi F, Chatterjee Aniruddha, Stockwell Peter A, Eccles Michael R, Macaulay Erin C
Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand.
Front Oncol. 2020 May 5;10:468. doi: 10.3389/fonc.2020.00468. eCollection 2020.
Transposable elements (TEs) have an established role as important regulators of early human development, functioning as tissue-specific genes and regulatory elements. Functional TEs are highly active during early development, and interact with important developmental genes, some of which also function as oncogenes. Dedifferentiation is a hallmark of cancer, and is characterized by genetic and epigenetic changes that enable proliferation, self-renewal and a metabolism reminiscent of embryonic stem cells. There is also compelling evidence suggesting that the path to dedifferentiation in cancer can contribute to invasion and metastasis. TEs are frequently expressed in cancer, and recent work has identified a newly proposed mechanism involving extensive recruitment of TE-derived promoters to drive expression of oncogenes and subsequently promote oncogenesis-a process termed onco-exaptation. However, the mechanism by which this phenomenon occurs, and the extent to which it contributes to oncogenesis remains unknown. Initial hypotheses have proposed that onco-exaptation events are cancer-specific and arise randomly due to the dysregulated and hypomethylated state of cancer cells and abundance of TEs across the genome. However, we suspect that exaptation-like events may not just arise due to chance activation of novel regulatory relationships as proposed previously, but as a result of the reestablishment of early developmental regulatory relationships. Dedifferentiation in cancer is well-documented, along with expression of TEs. The known interactions between TEs and pluripotency factors such as NANOG and OCTt4 during early development, along with the expression of some placental-specific TE-derived transcripts in cancer support a possible link between TEs and dedifferentiation of tumor cells. Thus, we hypothesize that onco-exaptation events can be associated with the epigenetic reawakening of early developmental TEs to regulate expression of oncogenes and promote oncogenesis. We also suspect that activation of these early developmental regulatory TEs may promote dedifferentiation, although at this stage it is hard to predict whether TE activation is one of the initial drivers of dedifferentiation. We expect that developmental TE activation occurs as a result of the establishment of an epigenetic landscape in cancer that resembles that of early development and that developmental TE activation may also enable cancers to exploit early developmental pathways, repurposing them to promote malignancy.
转座元件（TEs）作为人类早期发育的重要调节因子，发挥着既定作用，其功能类似于组织特异性基因和调控元件。功能性TEs在早期发育过程中高度活跃，并与重要的发育基因相互作用，其中一些发育基因还具有癌基因功能。去分化是癌症的一个标志，其特征在于遗传和表观遗传变化，这些变化使得癌细胞能够增殖、自我更新，并具有类似于胚胎干细胞的代谢特征。也有令人信服的证据表明，癌症中的去分化过程可能导致侵袭和转移。TEs在癌症中经常表达，最近的研究发现了一种新提出的机制，该机制涉及大量募集TE衍生的启动子以驱动癌基因的表达，进而促进肿瘤发生——这一过程被称为肿瘤适应性进化。然而，这种现象发生的机制以及它对肿瘤发生的贡献程度仍然未知。最初的假设提出，肿瘤适应性进化事件是癌症特异性的，由于癌细胞的失调和低甲基化状态以及基因组中TEs的丰富性而随机出现。然而，我们怀疑，适应性进化样事件可能不仅仅是如先前提出的那样由于新的调控关系的偶然激活而产生，而是早期发育调控关系重新建立的结果。癌症中的去分化以及TEs的表达都有充分的文献记载。在早期发育过程中，TEs与多能性因子如NANOG和OCTt4之间已知的相互作用，以及癌症中一些胎盘特异性TE衍生转录本的表达，支持了TEs与肿瘤细胞去分化之间可能存在的联系。因此，我们假设肿瘤适应性进化事件可能与早期发育TEs的表观遗传重新激活有关，从而调节癌基因的表达并促进肿瘤发生。我们还怀疑这些早期发育调控TEs的激活可能促进去分化，尽管在现阶段很难预测TE激活是否是去分化的初始驱动因素之一。我们预计，发育性TE激活是由于癌症中建立了类似于早期发育的表观遗传格局而发生的，并且发育性TE激活也可能使癌症能够利用早期发育途径，将其重新用于促进恶性肿瘤发展。
