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.
Given the enormous suffering and death associated with human cancers, there is an urgent need for novel therapeutic approaches to target tumor growth and metastasis. While initial efforts have focused on the dysregulated oncogenic program of cancer cells, recent focus has been on the modulation and targeting of many “cancer-friendly,” non-genetic tumor microenvironmental factors, which support and enable tumor progression and metastasis. Two prominent examples are anti-angiogenesis and immunotherapy that target tumor-supporting vascularization and the immune-suppressive tumor microenvironment (TME), respectively. Lately, there has been significant interest in the therapeutic potential of ferroptosis, a natural tumor suppression mechanism that normally occurs as a result of oxidative stress, iron imbalance, and accumulation of lipid peroxides. While numerous studies have identified various cell intrinsic mechanisms to protect or promote ferroptosis, the role of various TME stress factors are also recently recognized to modulate the tumor cells’ susceptibility to ferroptosis. This review aims to compile and highlight evidence of these factors, how various TME stresses affect ferroptosis, and their implications in various stages of tumor development and expected response to ferroptosis-triggering therapeutics under development. Consequently, understanding ways to enhance ferroptosis sensitivity both intracellularly and in the TME may optimize therapeutic sensitivity to minimize or prevent tumor growth and metastasis.
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