Colorectal cancer (CRC) is generally regarded as the third frequent malignancy worldwide, while current diagnosis and treatment of the disease are limited. The previous studies of CRC revealed that epigenetic modification plays a crucial role in the progression of CRC. Epigenetic modification is identified as heritable changes in gene functions that occur without changing the DNA sequence, resulting in cells with similar DNA eventually developing into different types with different functions, which encompasses DNA/RNA methylation, histone modification, and non-coding RNA regulation. Circular RNA (circRNA), a kind of non-coding RNA that forms a covalently closed loop, is widely present in various cells which drive initiation and progression of cancers through multiple pathways. The emerging data show that epigenetic modification may affect the biological functions of circRNA, while circRNA can also participate in the progression of CRC by targeting molecules related to epigenetic modification. N6-methyladenosine (m6A) has been found to directly promote production, translation, and functions of circRNA on the one hand, and interact with circRNA on the other hand, thereby altering onset, progression, and metastasis of the disease. DNA methylation and histone modification have also been observed to have potential interaction with circRNA. This review provides a brief overview about the association between current epigenetic modifications and circRNA, and the significant role they may play in the progression of CRC, and also outlines the potential applications to diagnosis and treatment, and the research direction in the future.
Keywords：circular RNA (circRNA)
;
colorectal cancer (CRC)
;
N6‑methyladenosine (m6A)
;
DNA methylation
;
histone modification
通常来说，circRNA是在细胞核中由线性mRNA剪切产生的产物，但许多circRNA却被发现在细胞质中发挥作用，这表明circRNA的功能可能与其亚细胞定位有关；而研究发现m6A修饰在circRNA核输出这一过程中发挥着重要作用。CHEN等［29］发现了一种结直肠癌转移到肝脏的新机制，其中YTHDC1介导m6A修饰的circNSUN2从细胞核输出至细胞质，随即结合胰岛素样生长因子2 mRNA结合蛋白2（insulin like growth factor 2 mRNA binding protein 2，IGF2BP2）形成三元复合物稳定HMGA2（high mobility group AT-hook 2） mRNA，最终促进了结直肠癌的肝转移。IGF2BP2是一种RNA结合蛋白；而HMGA2是肿瘤转移的驱动因素，并且早已被报道与结直肠癌的分期和转移相关。这项研究发现了circNSUN2类似mRNA的核输出机制，并强调了m6A修饰在这一过程中发挥的重要作用，是第一个揭示m6A修饰介导circRNA核输出的重要证据，表明了m6A修饰可以作为circRNA代谢的潜在选择性信号。此外，该研究还强调了YTHDC1在其中的重要作用，支持了既往人们提出的YTHDC1影响甲基化circRNA核输出的假设。
与m6A修饰调控circRNA作用相反，circRNA也可以调控m6A修饰及其调节因子，从而影响结直肠癌中的下游靶基因，进而影响疾病进展。YTHDF1是m6A修饰的调节因子，被发现在结直肠癌中高表达，并通过下游通路影响结直肠癌细胞的致瘤性和干细胞样活性［30］。一项研究［31］证明了YTHDF1在结直肠癌中可以被上游的circRNA和miRNA调控，其中circRNA充当ceRNA，降低其下游靶向YTHDF1的miRNA丰度，最终抑制结直肠癌增殖、迁移、侵袭和化学耐药的表型。IGF2BP2也是m6A修饰的调节因子，常被发现在结直肠癌中作为circRNA的下游分子发挥作用，影响疾病发展。YAO等［32］发现circEZH2一方面阻止IGF2BP2降解，另一方面作为miRNA海绵促进IGF2BP2翻译，致其蛋白水平上调，从而增强了cAMP反应元件结合蛋白1（cAMP responsive element binding protein 1，CREB1）mRNA的稳定性，最终促进结直肠癌进展。该研究表明了circRNA可以通过影响m6A的调节因子改变下游基因mRNA的稳定性，从而在结直肠癌的进展中发挥重要作用。虽然文章均提及了m6A修饰发挥作用的可能性，但遗憾的是，2项研究都没有论证circRNA通过m6A调节因子发挥作用的下游机制。
组蛋白修饰主要发生在组蛋白的N端，常见的包括乙酰化、甲基化、磷酸化、泛素化、ADP核糖基化、苏木化、去氨基化等［42］。目前已经发现一些circRNA可以在疾病中调节组蛋白修饰。EZH2（enhancer of zeste 2 polycomb repressive complex 2 subunit）是一种组蛋白赖氨酸甲基转移酶，通过对组蛋白的翻译后修饰以调节染色质结构，促进转录沉默［43］。WANG等［44］的研究发现，结直肠癌中的一种circRNA通过海绵化miR-600来上调EZH2表达，从而间接调节组蛋白甲基化；该研究提出了circRNA通过参与组蛋白修饰以影响基因表观遗传状态，进而影响疾病进程的机制。而另一项研究［45］发现，一种来自组蛋白甲基转移酶NSD2（nuclear receptor binding SET domain protein 2）基因的circRNA在结直肠癌的肝转移发展中发挥重要作用；该circRNA充当miRNA海绵影响后续通路而促进结直肠癌的迁移、侵袭和转移，提示circRNA通过影响组蛋白修饰的调节分子进一步调控疾病的潜在可能。
The review and collation of relevant articles was completed by PENG Tian. The idea of the paper was guided by XU Leiming. The manuscript was drafted and revised by PENG Tian and XU Leiming. Both authors have read and agreed to the submission of the final manuscript.
利益冲突声明
所有作者声明不存在利益冲突。
COMPETING INTERESTS
Both authors disclose no relevant conflict of interests.
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... 通常来说，circRNA是在细胞核中由线性mRNA剪切产生的产物，但许多circRNA却被发现在细胞质中发挥作用，这表明circRNA的功能可能与其亚细胞定位有关；而研究发现m6A修饰在circRNA核输出这一过程中发挥着重要作用.CHEN等［29］发现了一种结直肠癌转移到肝脏的新机制，其中YTHDC1介导m6A修饰的circNSUN2从细胞核输出至细胞质，随即结合胰岛素样生长因子2 mRNA结合蛋白2（insulin like growth factor 2 mRNA binding protein 2，IGF2BP2）形成三元复合物稳定HMGA2（high mobility group AT-hook 2） mRNA，最终促进了结直肠癌的肝转移.IGF2BP2是一种RNA结合蛋白；而HMGA2是肿瘤转移的驱动因素，并且早已被报道与结直肠癌的分期和转移相关.这项研究发现了circNSUN2类似mRNA的核输出机制，并强调了m6A修饰在这一过程中发挥的重要作用，是第一个揭示m6A修饰介导circRNA核输出的重要证据，表明了m6A修饰可以作为circRNA代谢的潜在选择性信号.此外，该研究还强调了YTHDC1在其中的重要作用，支持了既往人们提出的YTHDC1影响甲基化circRNA核输出的假设. ...
1
... 与m6A修饰调控circRNA作用相反，circRNA也可以调控m6A修饰及其调节因子，从而影响结直肠癌中的下游靶基因，进而影响疾病进展.YTHDF1是m6A修饰的调节因子，被发现在结直肠癌中高表达，并通过下游通路影响结直肠癌细胞的致瘤性和干细胞样活性［30］.一项研究［31］证明了YTHDF1在结直肠癌中可以被上游的circRNA和miRNA调控，其中circRNA充当ceRNA，降低其下游靶向YTHDF1的miRNA丰度，最终抑制结直肠癌增殖、迁移、侵袭和化学耐药的表型.IGF2BP2也是m6A修饰的调节因子，常被发现在结直肠癌中作为circRNA的下游分子发挥作用，影响疾病发展.YAO等［32］发现circEZH2一方面阻止IGF2BP2降解，另一方面作为miRNA海绵促进IGF2BP2翻译，致其蛋白水平上调，从而增强了cAMP反应元件结合蛋白1（cAMP responsive element binding protein 1，CREB1）mRNA的稳定性，最终促进结直肠癌进展.该研究表明了circRNA可以通过影响m6A的调节因子改变下游基因mRNA的稳定性，从而在结直肠癌的进展中发挥重要作用.虽然文章均提及了m6A修饰发挥作用的可能性，但遗憾的是，2项研究都没有论证circRNA通过m6A调节因子发挥作用的下游机制. ...
1
... 与m6A修饰调控circRNA作用相反，circRNA也可以调控m6A修饰及其调节因子，从而影响结直肠癌中的下游靶基因，进而影响疾病进展.YTHDF1是m6A修饰的调节因子，被发现在结直肠癌中高表达，并通过下游通路影响结直肠癌细胞的致瘤性和干细胞样活性［30］.一项研究［31］证明了YTHDF1在结直肠癌中可以被上游的circRNA和miRNA调控，其中circRNA充当ceRNA，降低其下游靶向YTHDF1的miRNA丰度，最终抑制结直肠癌增殖、迁移、侵袭和化学耐药的表型.IGF2BP2也是m6A修饰的调节因子，常被发现在结直肠癌中作为circRNA的下游分子发挥作用，影响疾病发展.YAO等［32］发现circEZH2一方面阻止IGF2BP2降解，另一方面作为miRNA海绵促进IGF2BP2翻译，致其蛋白水平上调，从而增强了cAMP反应元件结合蛋白1（cAMP responsive element binding protein 1，CREB1）mRNA的稳定性，最终促进结直肠癌进展.该研究表明了circRNA可以通过影响m6A的调节因子改变下游基因mRNA的稳定性，从而在结直肠癌的进展中发挥重要作用.虽然文章均提及了m6A修饰发挥作用的可能性，但遗憾的是，2项研究都没有论证circRNA通过m6A调节因子发挥作用的下游机制. ...
1
... 与m6A修饰调控circRNA作用相反，circRNA也可以调控m6A修饰及其调节因子，从而影响结直肠癌中的下游靶基因，进而影响疾病进展.YTHDF1是m6A修饰的调节因子，被发现在结直肠癌中高表达，并通过下游通路影响结直肠癌细胞的致瘤性和干细胞样活性［30］.一项研究［31］证明了YTHDF1在结直肠癌中可以被上游的circRNA和miRNA调控，其中circRNA充当ceRNA，降低其下游靶向YTHDF1的miRNA丰度，最终抑制结直肠癌增殖、迁移、侵袭和化学耐药的表型.IGF2BP2也是m6A修饰的调节因子，常被发现在结直肠癌中作为circRNA的下游分子发挥作用，影响疾病发展.YAO等［32］发现circEZH2一方面阻止IGF2BP2降解，另一方面作为miRNA海绵促进IGF2BP2翻译，致其蛋白水平上调，从而增强了cAMP反应元件结合蛋白1（cAMP responsive element binding protein 1，CREB1）mRNA的稳定性，最终促进结直肠癌进展.该研究表明了circRNA可以通过影响m6A的调节因子改变下游基因mRNA的稳定性，从而在结直肠癌的进展中发挥重要作用.虽然文章均提及了m6A修饰发挥作用的可能性，但遗憾的是，2项研究都没有论证circRNA通过m6A调节因子发挥作用的下游机制. ...
