Background: Drug resistance severely reduces treatment efficiency of chemotherapy and leads to poor prognosis. However, regulatory factors of chemoresistant cancer cells are largely unknown.

Methods: The expression of estrogen receptor related receptors (ERRs) in chemoresistant cancer cells are checked. The roles of ERRγ in chemoresistance are confirmed by in vitro and in vivo studies. The mechanisms responsible for ERRγ-regulated expression of ABCB1 and CPT1B are investigated.

Results: The expression of ERRγ is upregulated in chemoresistant cancer cells. Targeted inhibition of ERRγ restores the chemosensitivity. ERRγ can directly bind to the promoter of ABCB1 to increase its transcription. An elevated interaction between ERRγ and p65 in chemoresistant cells further strengthens transcription of ABCB1. Further, ERRγ can increase the fatty acid oxidation (FAO) in chemoresistant cells via regulation of CPT1B, the rate-limiting enzyme of FAO. The upregulated ERRγ in chemoresistant cancer cells might be due to increased levels of N6-methyladenosine (m⁶A) can trigger the splicing of precursor ESRRG mRNA.

Conclusions: m⁶A induced ERRγ confers chemoresistance of cancer cells through upregulation of ABCB1 and CPT1B.

背景：耐药性严重降低化疗的治疗效率并导致预后不良。然而，化疗耐药癌细胞的调节因素在很大程度上是未知的。

方法：检查化疗耐药癌细胞中雌激素受体相关受体（ERR）的表达。ERRγ 在化疗耐药中的作用已通过体外和体内研究得到证实。研究了ERRγ 调节ABCB1和CPT1B表达的机制。

结果：ERRγ 的表达在化疗耐药癌细胞中上调。靶向抑制 ERRγ 可恢复化疗敏感性。ERRγ可以直接结合ABCB1的启动子以增加其转录。化疗耐药细胞中 ERRγ 和 p65 之间增强的相互作用进一步增强了ABCB1的转录。此外，ERRγ 可以通过调节CPT1B （ FAO 的限速酶）来增加化疗耐药细胞中的脂肪酸氧化 (FAO) 。化疗耐药癌细胞中 ERRγ 上调可能是由于 N6-甲基腺苷 (m ^{6 A) 水平增加可以触发前体}ESRRG mRNA的剪接。

结论：m ^{6 A 诱导的 ERRγ 通过上调}ABCB1和CPT1B赋予癌细胞化疗耐药性。