Abstract 2667: Genetic removal of metazoan SpoT homolog I (MESH1) inhibits proliferation through the repression of HIPPO effector TAZ

The capacity of tumor cells to survive various stresses is an essential property that endows them invulnerability. One of the bacterial key adaptive strategies against nutrient deprivation is stringent response. In bacteria, nutrient deprivation leads to an elevation of a signaling alarmone, guanosine tetraphosphate ((p)ppGpp) to repress the protein synthesis and proliferation activity in order to maintain cell viability. The accumulation of (p)ppGpp is partially caused by the repression of its hydrolase, SpoT. However, this strategy still remains elusive in humans, but the human ortholog of SpoT-MESH1 has been discovered. MESH1 also has the hydrolase activity on (p)ppGpp in vitro, but human cells lack the required alarmone (p)ppGpp and its synthetase, which restricts the discovery of stringent response in humans. Unexpectedly, our recent data suggests that MESH1 depletion allows cell survival under cystine deprivation, an extremely oxidative stress, yet with a slow proliferation rate. These correspond to bacterial stringent response phenotypes. Moreover, our gene expression profiling shows that MESH1 silencing triggers a global transcriptional reprogramming with a similarity to bacterial transcriptional responses of stringent response. Altogether, these evidences inspire us to speculate on the existence of human stringent response with similar cell protective functions, albeit in the absence of (p)ppGpp. In this study, I aim to identify the molecular pathways and regulatory mechanisms that MESH1 adopts to explain the MESH1-related stringent response phenotypes in human cancer cell lines. One interesting phenomenon we observed from our genome-wide RNA screen is that MESH1 silencing significantly represses TAZ RNA level. TAZ serves as a key co-activator involved in the HIPPO pathway that has been well studied to regulate cell proliferation, cell stemness, and etc, which are perfectly relevant to the MESH1-related stringent response phenotypes. Therefore, I will specifically determine the functional roles of TAZ repression upon MESH1 removal in the expression of stringent response features by genetic tools. Furthermore, I will characterize the transcriptional control of TAZ and other gene signatures of human stringent response. We observed that MESH1 depletion significantly represses the acetyl-CoA:CoA ratio and further inhibits the histone acetylation activity that presumably turns off/on certain gene transcription. Based on these facts, I will determine the importance of histone modification on the transcriptional reprogramming upon MESH1 silencing. Successful completion of this study will equip us with more thorough understandings of stress response mechanisms in humans so that we can improve the treatment for stress-related diseases, such as cancer, by providing a novel therapeutic target, MESH1. Note: This abstract was not presented at the meeting. Citation Format: Tianai Sun, Chien-Kuang Ding, Jen-Tsan A. Chi. Genetic removal of metazoan SpoT homolog I (MESH1) inhibits proliferation through the repression of HIPPO effector TAZ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2667.