1. Zhang Lu
Nat Cell Biol. 2016 Oct;18(10):

2. 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 Oct;18(10):
Highlighted by Nature Reviews Cancer 16, 678 (2016).
2. IKKβ promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3. Genes & Development Aug 15;30 (16):
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, (2):
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,

3. Background

4. 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

6. Tumour core regions display low glutamine and αKG levels

7. 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

8. Low glutamine leads to dedifferentiation in tumour cores

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

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

11. 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

12. 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

13. Low glutamine leads to dedifferentiation in tumour cores

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

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

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

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

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

19. Low glutamine level leads to increased histone methylation in tumour cells

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

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

27. 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

28. 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

29. 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

30. 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

31. 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，

32. 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

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

34. 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

35. Thank You