MESH1 knockdown triggers proliferation arrest through TAZ repression
Abstract
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 transcriptome. While mammalian genomes encode MESH1—the homolog of the (p)ppGpp hydrolase SpoT, current knowledge about its function remains limited. We found MESH1 expression tended to be higher in tumors and associated with poor patient outcomes. Consistently, MESH1 knockdown robustly inhibited proliferation, depleted dNTPs, reduced tumor sphere formation, and retarded xenograft growth. These antitumor phenotypes associated with MESH1 knockdown were accompanied by a significantly altered transcriptome, including the repressed expression of TAZ, a HIPPO coactivator, and proliferative gene. Importantly, TAZ restoration mitigated many anti-growth phenotypes of MESH1 knockdown, including proliferation arrest, reduced sphere formation, tumor growth inhibition, dNTP depletion, 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 10, 2022
- Source ID
- 10.1038/s41419-022-04663-6
Entities
People
- Baek Kim
- Caitlin Shepard
- Chao-Chieh Lin
- Chien-kuang Cornelia Ding
- Everardo Macias
- Jen-Tsan A Chi
- Jianli Wu
- Pei Zhou
- Raluca Gordân
- Si’ana Coggins
- Tianai Sun
- Yang Zhang
- Yasaman Setayeshpour
- Yuning Zhang
Organizations
- National Institutes of Health
- United States Department of Defense
- United States Department of Health and Human Services