The epigenome involves a complex set of cellular processes governing genomic activity. Dissecting this complexity necessitates the development of tools capable of specifically manipulating these processes. The repurposing of prokaryotic CRISPR systems has allowed for the development of diverse technologies for epigenome engineering. Here, we review the state of currently achievable epigenetic manipulations along with corresponding applications. With future optimization, CRISPR-based epigenomic editing stands as a set of powerful tools for understanding and controlling biological function. <<<

Ryan T Davis, Kerrigan Blake, Dennis Ma, Mari B Ishak Gabra, Grace A Hernandez, Anh T Phung, Ying Yang, Dustin Maurer, Austin E Y T Lefebvre, Hamad Alshetaiwi, Zhengtao Xiao, Juan Liu, Jason W Locasale, Michelle A Digman, Eric Mjolsness, Mei Kong, Zena Werb, Devon A Lawson <<<

Although metastasis remains the cause of most cancer-related mortality, mechanisms governing seeding in distal tissues are poorly understood. Here, we establish a robust method for the identification of global transcriptomic changes in rare metastatic cells during seeding using single-cell RNA sequencing and patient-derived-xenograft models of breast cancer. We find that both primary tumours and micrometastases display transcriptional heterogeneity but micrometastases harbour a distinct transcriptome program conserved across patient-derived-xenograft models that is highly predictive of poor survival of patients. Pathway analysis revealed mitochondrial oxidative phosphorylation as the top pathway upregulated in micrometastases, in contrast to higher levels of glycolytic enzymes in primary tumour cells, which we corroborated by flow cytometric and metabolomic analyses. Pharmacological inhibition of oxidative phosphorylation dramatically attenuated metastatic seeding in the lungs, which demonstrates the functional importance of oxidative phosphorylation in metastasis and highlights its potential as a therapeutic target to prevent metastatic spread in patients with breast cancer. <<<

Hai-Liang Zhang, Bing-Xin Hu, Zhi-Ling Li, Tian Du, Jia-Lu Shan, Zhi-Peng Ye, Xiao-Dan Peng, Xuan Li, Yun Huang, Xian-Ying Zhu, Yu-Hong Chen, Gong-Kan Feng, Dajun Yang, Rong Deng, Xiao-Feng Zhu <<<

The accumulation of lipid peroxides is recognized as a determinant of the occurrence of ferroptosis. However, the sensors and amplifying process of lipid peroxidation linked to ferroptosis remain obscure. Here we identify PKCβII as a critical contributor of ferroptosis through independent genome-wide CRISPR-Cas9 and kinase inhibitor library screening. Our results show that PKCβII senses the initial lipid peroxides and amplifies lipid peroxidation linked to ferroptosis through phosphorylation and activation of ACSL4. Lipidomics analysis shows that activated ACSL4 catalyses polyunsaturated fatty acid-containing lipid biosynthesis and promotes the accumulation of lipid peroxidation products, leading to ferroptosis. Attenuation of the PKCβII-ACSL4 pathway effectively blocks ferroptosis in vitro and impairs ferroptosis-associated cancer immunotherapy in vivo. Our results identify PKCβII as a sensor of lipid peroxidation, and the lipid peroxidation-PKCβII-ACSL4 positive-feedback axis may provide potential targets for ferroptosis-associated disease treatment. <<<

De Huang, Yan Wang, J Will Thompson, Tao Yin, Peter B Alexander, Diyuan Qin, Poorva Mudgal, Haiyang Wu, Yaosi Liang, Lianmei Tan, Christopher Pan, Lifeng Yuan, Ying Wan, Qi-Jing Li, Xiao-Fan Wang <<<

Many cancers have an unusual dependence on glutamine. However, most previous studies have focused on the contribution of glutamine to metabolic building blocks and the energy supply. Here, we report that cancer cells with aberrant expression of glutamate decarboxylase 1 (GAD1) rewire glutamine metabolism for the synthesis of γ-aminobutyric acid (GABA)-a prominent neurotransmitter-in non-nervous tissues. An analysis of clinical samples reveals that increased GABA levels predict poor prognosis. Mechanistically, we identify a cancer-intrinsic pathway through which GABA activates the GABA receptor to inhibit GSK-3β activity, leading to enhanced β-catenin signalling. This GABA-mediated β-catenin activation both stimulates tumour cell proliferation and suppresses CD8 T cell intratumoural infiltration, such that targeting GAD1 or GABAR in mouse models overcomes resistance to anti-PD-1 immune checkpoint blockade therapy. Our findings uncover a signalling role for tumour-derived GABA beyond its classic function as a neurotransmitter that can be targeted pharmacologically to reverse immunosuppression. <<<