Chi, Jen-Tsan AshleySun, Tianai2022-06-152022-06-152022https://hdl.handle.net/10161/25151<p>All organisms are constantly exposed to various stresses, necessitating adaptive strategies for survival. In bacteria, the main stress-coping mechanism is the stringent response triggered by the accumulation of “alarmone” (p)ppGpp to arrest proliferation and reprogram the transcriptome. While mammalian genomes encode MESH1—the homologue of the (p)ppGpp hydrolase SpoT, current knowledge about its function remains limited. We found MESH1 expression tended to be higher in tumors and is associated with poor patient outcomes. Consistently, MESH1 knockdown robustly inhibited proliferation, depleted dNTPs, reduced tumorsphere formation, and retarded xenograft growth. These anti-tumor phenotypes associated with MESH1 knockdown were accompanied by a significantly altered transcriptome, including the repressed mRNA expression of TAZ, a HIPPO co-activator mediating the expression of many proliferative genes. Importantly, TAZ restoration mitigated many anti-growth phenotypes of MESH1 knockdown, including proliferation arrest, sphere formation inhibition, dNTP depletion, retarded xenograft growth and transcriptional changes. Furthermore, TAZ repression was associated with the histone hypo-acetylation at TAZ regulatory loci due to the induction of epigenetic repressors HDAC5 and AHRR. Together, MESH1 knockdown in human cells altered the genome-wide transcriptional patterns and arrested proliferation that mimicked the bacterial stringent response through the epigenetic repression of TAZ expression.</p>BiologyMESH1stringent responseTAZDissertation