Jin Heping, Chen Yanlian, Ren Jian, Huang Junjiu, Zhao Yong, Liu Haiying
MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
Sci China Life Sci. 2022 Dec;65(12):2505-2516. doi: 10.1007/s11427-021-2085-9. Epub 2022 Jun 1.
TERC is the RNA component of telomerase, and provides a template for TERT to synthesize telomere repeats at chromosome ends. Increasing evidence has revealed that TERC is involved in other biological processes beyond telomerase. Here, we found that the expression level of TERC is negatively correlated with PD-L1 and that ectopic expression of TERC but not TERT in ALT cells significantly inhibits PD-L1, suggesting that TERC suppresses PD-L1 expression in a telomerase-independent manner. Mechanistically, instead of regulating PD-L1 mRNA directly, TERC accelerates PD-L1 mRNA degradation by inhibiting the expression of HuR, which binds to the 3'UTR of PD-L1 mRNA and maintains its stability. We also found that the small molecule AS1842856, a FoxO1 inhibitor, promotes TERC expression and reverses the PD-L1 upregulation caused by chemotherapy, providing a potential combination cancer therapy that avoids cancer immune escape during chemotherapy.
TERC是端粒酶的RNA成分，为端粒酶逆转录酶（TERT）在染色体末端合成端粒重复序列提供模板。越来越多的证据表明，TERC参与了端粒酶以外的其他生物学过程。在此，我们发现TERC的表达水平与程序性死亡受体配体1（PD-L1）呈负相关，并且在替代端粒延长（ALT）细胞中异位表达TERC而非TERT可显著抑制PD-L1，这表明TERC以不依赖端粒酶的方式抑制PD-L1表达。机制上，TERC并非直接调节PD-L1 mRNA，而是通过抑制HuR的表达来加速PD-L1 mRNA的降解，HuR可与PD-L1 mRNA的3'非翻译区（3'UTR）结合并维持其稳定性。我们还发现，小分子AS1842856（一种叉头框蛋白O1（FoxO1）抑制剂）可促进TERC表达，并逆转化疗引起的PD-L1上调，这为避免化疗期间癌症免疫逃逸提供了一种潜在的联合癌症治疗方法。
