Zhang Lu 2017.06.17 Nat Cell Biol. 2016 Oct;18(10):1090-101

Department of Cancer Biology, Ph.D. Associate Professor, Dr. Mei Kong Department of Cancer Biology, Beckman Research Institute of City of Hope Cancer Center Research Focus : Cancer Biology Cell Signaling Cancer Metabolism 1. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat Cell Biol. 2016 Oct;18(10):1090-101. Highlighted by Nature Reviews Cancer 16, 678 (2016). 2. IKKβ promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3. Genes & Development. 2016 Aug 15;30 (16):1837-51. Highlighted by Nature Reviews Cancer 16, 617 (2016). 3. The B55a subunit of PP2A drives a p53-dependent metabolic adaptation to glutamine deprivation. Molecular Cell, 2013 50(2):200-211. 4. Alpha4 is an essential regulator of PP2A phosphatase activity. Molecular Cell, 2009, 36:51-60. 5. The PP2A-associated protein Alpha4 is an essential inhibitor of apoptosis. Science 2004, 306, 695-8.

Background

Contents Tumour core regions display low glutamine and αKG levels Low glutamine leads to dedifferentiation and drug resistance in tumour cores and tumor cells Tumour core regions display hypermethylation of histone H3 Low-glutamine-induced dedifferentiation and drug resistance is mediated by histone methylation on H3K27

Tumour core regions display low glutamine and αKG levels

ADSC：Human adipose tissue-derived stem cells Low glutamine leads to dedifferentiation in tumour cores Glutamine缺乏抑制脂肪细胞分化 ADSC：Human adipose tissue-derived stem cells 3T3-L1：mouse pre-adipocytes

Low glutamine leads to dedifferentiation in tumour cores

Low glutamine leads to dedifferentiation in tumour cores Glutamine缺乏诱导CD271表达 CD271, CD133：markers for dedifferentiation

Low glutamine leads to dedifferentiation in tumour cores 提供Glutamine或αKG能够逆转CD271表达

Low glutamine leads to dedifferentiation in tumour cores CD271,CD133阳性细胞由阴性细胞 去分化产生 CD271, CD133：markers for dedifferentiation

Compound 968：glutaminase inhibitor Low glutamine leads to dedifferentiation in tumour cores 抑制glutamine代谢能够模拟glutamine缺乏的效果 Compound 968：glutaminase inhibitor

Low glutamine leads to dedifferentiation in tumour cores

Low-glutamine-induced dedifferentiation results in resistance to BRAF inhibitor treatment PLX4032：BRAF inhibitor

Conclusions Tumour core regions display low glutamine and αKG levels Low glutamine leads to dedifferentiation and drug resistance in tumour cores and tumor cells

HDM (histone demethylases) α-KG HDM (histone demethylases) Nature. 2015 Feb 19;518(7539):413-6

Tumour core regions display hypermethylation of histone H3 肿瘤中心区域甲基化水平升高

Tumour core regions display hypermethylation of histone H3 肿瘤中心区域甲基化水平升高

Low glutamine level leads to increased histone methylation in tumour cells

Low glutamine level leads to increased histone methylation in tumour cells Glutamine缺乏的肿瘤细胞补充α-KG后甲基化水平降低

DON, Compound 968：glutaminase inhibitors Low glutamine level leads to increased histone methylation in tumour cells 抑制glutamine代谢能够模拟glutamine缺乏的效果 DON, Compound 968：glutaminase inhibitors

Compound 968：glutaminase inhibitor Low glutamine level leads to increased histone methylation in tumour core regions 抑制glutamine代谢能够模拟glutamine缺乏的效果 Compound 968：glutaminase inhibitor

EAA, essential amino acid Low glutamine level leads to increased histone methylation in tumour cells 只有Glutamine缺乏和hypoxia能够诱导甲基化 EAA, essential amino acid

Conclusions Tumour core regions display low glutamine and αKG levels Low glutamine leads to dedifferentiation and drug resistance in tumour cores and tumor cells Tumour core regions display hypermethylation of histone H3

Low-glutamine-induced dedifferentiation is mediated by histone methylation on H3K27 Adox，DZNep： global histone methylation inhibitors， EPZ005687：H3K27me3 inhibitor， BRD4770，UNC0638： H3K9 methylation inhibitors

Low-glutamine-induced dedifferentiation is mediated by histone methylation on H3K27 EPZ005687：H3K27me3 inhibitor，

KDM6B：H3K27-specific demethylase EZH2：H3K27 methyltransferase Low-glutamine-induced dedifferentiation is mediated by histone methylation on H3K27 干扰KDM6B促进去分化， 干扰EZH2抑制去分化过程 KDM6B：H3K27-specific demethylase EZH2：H3K27 methyltransferase

Low-glutamine-induced dedifferentiation is mediated by histone methylation on H3K27 通过干扰EZH2抑制H3K27甲基化能够重新诱导分化相关基因转录

Low-glutamine-induced dedifferentiation is mediated by histone methylation on H3K27 Glutamine缺乏能够诱导H3K27me3与分化相关基因转录区域结合

Conclusions Tumour core regions display low glutamine and αKG levels Low glutamine leads to dedifferentiation and drug resistance in tumour cores and tumor cells Tumour core regions display hypermethylation of histone H3

Low-glutamine-induced drug resistance is mediated by histone methylation on H3K27 抑制H3K27甲基化能够逆转Glutamine缺乏导致的耐药 DZNep： global histone methylation inhibitor， EPZ005687：H3K27me3 inhibitor，

KDM6B：H3K27-specific demethylase EZH2：H3K27 methyltransferase Low-glutamine-induced drug resistance is mediated by histone methylation on H3K27 干扰KDM6B能够增强肿瘤细胞耐药， 干扰EZH2能够抑制肿瘤细胞耐药 KDM6B：H3K27-specific demethylase EZH2：H3K27 methyltransferase

Low-glutamine-induced drug resistance is mediated by histone methylation on H3K27 DZNep： global histone methylation inhibitor， EPZ005687：H3K27me3 inhibitor， PLX4032：BRAF inhibitor

Conclusions Tumour core regions display low glutamine and αKG levels Low glutamine leads to dedifferentiation and drug resistance in tumour cores and tumor cells Tumour core regions display hypermethylation of histone H3 Low-glutamine-induced dedifferentiation and drug resistance is mediated by histone methylation on H3K27

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