TERC suppresses PD-L1 expression by downregulating RNA binding protein HuR
TERC suppresses PD-L1 expression by downregulating RNA binding protein HuR
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DOI：
10.1007/s11427-021-2085-9
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发表时间：
2022-06
期刊：
影响因子：
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通讯作者：
Heping Jin;Yanlian Chen;Jian Ren;Junjiu Huang;Yong Zhao;Haiying Liu
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作者：
Heping Jin;Yanlian Chen;Jian Ren;Junjiu Huang;Yong Zhao;Haiying Liu
TERC是端粒酶的RNA组分，为TERT在染色体末端合成端粒重复序列提供了模板。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。在这里，我们发现TERC的表达水平与PD-L1呈负相关，并且在ALT细胞中异位表达TERC而不是TERT显著抑制PD-L1的表达，这表明TERC以端粒酶非依赖性的方式抑制PD-L1的表达。在机制上，TERC不是直接调节PD-L1mRNA，而是通过抑制Hur的表达来加速PD-L1mRNA的降解，Hur与PD-L1mRNA的3‘UTR结合并维持其稳定性。我们还发现，FoxO1抑制剂小分子AS1842856促进了TERC的表达，并逆转了化疗引起的PD-L1上调，提供了一种潜在的联合癌症治疗方法，可避免化疗期间的癌症免疫逃逸。
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.