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MESH1 knockdown triggers proliferation arrest through TAZ repression.

Publication ,  Journal Article
Sun, T; Ding, C-KC; Zhang, Y; Zhang, Y; Lin, C-C; Wu, J; Setayeshpour, Y; Coggins, S; Shepard, C; Macias, E; Kim, B; Zhou, P; Gordân, R; Chi, J-T
Published in: Cell Death Dis
March 10, 2022

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.

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Published In

Cell Death Dis

DOI

EISSN

2041-4889

Publication Date

March 10, 2022

Volume

13

Issue

3

Start / End Page

221

Location

England

Related Subject Headings

  • Transcription Factors
  • Mammals
  • Humans
  • Guanosine Pentaphosphate
  • Cell Proliferation
  • Animals
  • Acetylation
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis
 

Citation

APA
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Sun, T., Ding, C.-K., Zhang, Y., Lin, C.-C., Wu, J., Setayeshpour, Y., … Chi, J.-T. (2022). MESH1 knockdown triggers proliferation arrest through TAZ repression. Cell Death Dis, 13(3), 221. https://doi.org/10.1038/s41419-022-04663-6
Sun, Tianai, Chien-Kuang Cornelia Ding, Yuning Zhang, Yang Zhang, Chao-Chieh Lin, Jianli Wu, Yasaman Setayeshpour, et al. “MESH1 knockdown triggers proliferation arrest through TAZ repression.Cell Death Dis 13, no. 3 (March 10, 2022): 221. https://doi.org/10.1038/s41419-022-04663-6.
Sun T, Ding C-KC, Zhang Y, Lin C-C, Wu J, Setayeshpour Y, et al. MESH1 knockdown triggers proliferation arrest through TAZ repression. Cell Death Dis. 2022 Mar 10;13(3):221.
Sun, Tianai, et al. “MESH1 knockdown triggers proliferation arrest through TAZ repression.Cell Death Dis, vol. 13, no. 3, Mar. 2022, p. 221. Pubmed, doi:10.1038/s41419-022-04663-6.
Sun T, Ding C-KC, Zhang Y, Lin C-C, Wu J, Setayeshpour Y, Coggins S, Shepard C, Macias E, Kim B, Zhou P, Gordân R, Chi J-T. MESH1 knockdown triggers proliferation arrest through TAZ repression. Cell Death Dis. 2022 Mar 10;13(3):221.

Published In

Cell Death Dis

DOI

EISSN

2041-4889

Publication Date

March 10, 2022

Volume

13

Issue

3

Start / End Page

221

Location

England

Related Subject Headings

  • Transcription Factors
  • Mammals
  • Humans
  • Guanosine Pentaphosphate
  • Cell Proliferation
  • Animals
  • Acetylation
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis