Regulation of autophagic response by CNOT11 via IL-6/JAK/STAT signaling

While the CCR4-NOT complex is a key player of deadenylation-mediated mRNA degradation, the roles of its component CNOT11 remain elusive. Recent clinical studies have shown that CNOT11 is highly expressed in certain cancer types, and the elevated expression is associated with poor survival in cancer patients. In this study, we investigate the role of CNOT11 in cell viability, proliferation and mRNA degradation in tumor cells. Suppression of CNOT11 in HeLa cells leads to decreased expression of CCR4-NOT subunits and induces autophagy through the AMPK/ULK1 pathway. Transcriptomic and biochemical analyses reveal an activation of the JAK-STAT signaling pathway in CNOT11-knockdown (CNOT11-KD) cells, accompanied by increased IL-6 expression that contributes to autophagy. The increase of IL-6 is caused by an enhanced transcription rather than impaired deadenylation. We also find that proliferation of HeLa cells is significantly retarded, and cells are more sensitive to adriamycin treatment upon CNOT11-KD. These findings suggest that CNOT11 modulates cancer cell viability through regulation of cytokine production at the transcriptional level, implicating CNOT11 as a potential pharmacological target against cancer.