IFRD1 promotes tumor cells "low-cost" survival under glutamine starvation via inhibiting histone H1.0 nucleophagy.
Yabin HuangFanzheng MengTaofei ZengRick Francis ThorneLifang HeQingrui ZhaHairui LiHong LiuChuandong LangWanxiang XiongShixiang PanDalong YinMian WuXuedan SunLian-Xin LiuPublished in: Cell discovery (2024)
Glutamine addiction represents a metabolic vulnerability of cancer cells; however, effective therapeutic targeting of the pathways involved remains to be realized. Here, we disclose the critical role of interferon-related developmental regulator 1 (IFRD1) in the adaptive survival of hepatocellular carcinoma (HCC) cells during glutamine starvation. IFRD1 is induced under glutamine starvation to inhibit autophagy by promoting the proteasomal degradation of the key autophagy regulator ATG14 in a TRIM21-dependent manner. Conversely, targeting IFRD1 in the glutamine-deprived state increases autophagy flux, triggering cancer cell exhaustive death. This effect largely results from the nucleophilic degradation of histone H1.0 and the ensuing unchecked increases in ribosome and protein biosynthesis associated with globally enhanced chromatin accessibility. Intriguingly, IFRD1 depletion in preclinical HCC models synergizes with the treatment of the glutaminase-1 selective inhibitor CB-839 to potentiate the effect of limiting glutamine. Together, our findings reveal how IFRD1 supports the adaptive survival of cancer cells under glutamine starvation, further highlighting the potential of IFRD1 as a therapeutic target in anti-cancer applications.
Keyphrases
- cell death
- signaling pathway
- endoplasmic reticulum stress
- low cost
- oxidative stress
- induced apoptosis
- dna damage
- genome wide
- climate change
- drug delivery
- free survival
- cell cycle arrest
- dendritic cells
- diabetic rats
- risk assessment
- pi k akt
- cell therapy
- binding protein
- combination therapy
- amino acid
- replacement therapy