N6-methyladenine- induced LINC00667 promoted breast cancer progression through m6A/KIAA1429 positive feedback loop

Increasing evidence supports that N⁶-methyladenine (m⁶A) and long noncoding RNAs (lncRNAs) both act as master regulators involved in breast cancer (BC) tumorigenesis at epigenetic modification level. Here, our research tries to unveil the interaction of m⁶A and lncRNAs on BC progression and explore the underlying regulatory mechanism. In the current study, we found that LINC00667 was m⁶A-modified lncRNA, which was up-regulated upon the overexpression of KIAA1429. The high expression of LINC00667 was correlated with the prognosis of BC patients. Bio-functional assays indicated that LINC00667 promoted the proliferation and migration of BC cells. Mechanistic assays illustrated that KIAA1429 targeted the m⁶A modification site of LINC00667 and enhanced its mRNA stability. Moreover, LINC00667 positively regulated the KIAA1429 via sponging miR-556-5p, forming a KIAA1429/m⁶A/LINC00667/miR-556-5p feedback loop. Collectively, the central findings of our study suggest that KIAA1429-induced LINC00667 exerted its functions as an oncogene in BC progression through m⁶A-dependent feedback loop.

越来越多的研究证据表明，N⁶-甲基腺嘌呤（N⁶-methyladenine，m⁶A）与长链非编码RNA（long noncoding RNAs，lncRNAs）均在表观遗传修饰层面作为核心调控因子参与乳腺癌（breast cancer，BC）的发生发展。本研究旨在揭示m⁶A与lncRNAs在乳腺癌进展中的相互作用，并探索其潜在的调控机制。本研究发现，LINC00667是一种经m⁶A修饰的长链非编码RNA，其表达在KIAA1429过表达时会上调。LINC00667的高表达与乳腺癌患者的预后密切相关。生物学功能实验结果显示，LINC00667可促进乳腺癌细胞的增殖与迁移。机制实验表明，KIAA1429靶向结合LINC00667的m⁶A修饰位点，增强其mRNA稳定性。此外，LINC00667通过海绵吸附miR-556-5p正向调控KIAA1429，形成KIAA1429/m⁶A/LINC00667/miR-556-5p反馈环路。综上，本研究的核心发现提示，KIAA1429诱导的LINC00667可通过m⁶A依赖的反馈环路在乳腺癌进展中发挥致癌基因的功能。