TY - JOUR
T1 - α-Ketoglutarate links p53 to cell fate during tumour suppression
AU - Morris, John P.
AU - Yashinskie, Jossie J.
AU - Koche, Richard
AU - Chandwani, Rohit
AU - Tian, Sha
AU - Chen, Chi Chao
AU - Baslan, Timour
AU - Marinkovic, Zoran S.
AU - Sánchez-Rivera, Francisco J.
AU - Leach, Steven D.
AU - Carmona-Fontaine, Carlos
AU - Thompson, Craig B.
AU - Finley, Lydia W.S.
AU - Lowe, Scott W.
N1 - Funding Information:
Acknowledgements We thank members of the Lowe and Finley laboratory. Pancreatic intraepithelial neoplasia and PDAC tissue microarrays were generated by G. Askan and O. Basturk, and were generously provided as a resource from the David M. Rubenstein Center for Pancreatic Cancer Research. J.P.M. IV was supported by an American Cancer Society Postdoctoral Fellowship (126337-PF-14-066-01-TBE). J.J.Y. is supported by a T32 training grant from the NICHD (T32HD060600). F.J.S.-R. is an HHMI Hanna Gray Fellow and was partially supported by an MSKCC Translational Research Oncology Training Fellowship (NIH T32-CA160001). S.D.L. is supported by NIH grant (NIH R01CA204228). R.C. is supported by an American Association for Cancer Research/Pancreatic Cancer Action Network Pathway to Leadership Award. T.B. is supported by the William C. and Joyce C. O'Neil Charitable Trust and Memorial Sloan Kettering Single Cell Sequencing Initiative. C.C.-F is supported by NIH grant (NIH R00CA191021). L.W.S.F. is a Dale F. Frey-William Raveis Charitable Fund Scientist supported by the Damon Runyon Cancer Research Foundation (DFS-23-17) and a Searle Scholar. S.W.L. is an investigator in the Howard Hughes Medical Institute. This work was additionally supported by a Lustgarten Research Investigator Award (S.W.L.), a Program Program Project grant from the National Cancer Institute (S.W.L.), research grants from the Emerson Collective (S.W.L.), the Starr Cancer Consortium (I11-039 and I12-0051 L.W.S.F.), the Concern Foundation (L.W.S.F.), the Anna Fuller Fund (L.W.S.F.) and the Memorial Sloan Kettering Cancer Center Support Grant P30 CA008748.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/9/26
Y1 - 2019/9/26
N2 - The tumour suppressor TP53 is mutated in the majority of human cancers, and in over 70% of pancreatic ductal adenocarcinoma (PDAC)1,2. Wild-type p53 accumulates in response to cellular stress, and regulates gene expression to alter cell fate and prevent tumour development2. Wild-type p53 is also known to modulate cellular metabolic pathways3, although p53-dependent metabolic alterations that constrain cancer progression remain poorly understood. Here we find that p53 remodels cancer-cell metabolism to enforce changes in chromatin and gene expression that favour a premalignant cell fate. Restoring p53 function in cancer cells derived from KRAS-mutant mouse models of PDAC leads to the accumulation of α-ketoglutarate (αKG, also known as 2-oxoglutarate), a metabolite that also serves as an obligate substrate for a subset of chromatin-modifying enzymes. p53 induces transcriptional programs that are characteristic of premalignant differentiation, and this effect can be partially recapitulated by the addition of cell-permeable αKG. Increased levels of the αKG-dependent chromatin modification 5-hydroxymethylcytosine (5hmC) accompany the tumour-cell differentiation that is triggered by p53, whereas decreased 5hmC characterizes the transition from premalignant to de-differentiated malignant lesions that is associated with mutations in Trp53. Enforcing the accumulation of αKG in p53-deficient PDAC cells through the inhibition of oxoglutarate dehydrogenase—an enzyme of the tricarboxylic acid cycle—specifically results in increased 5hmC, tumour-cell differentiation and decreased tumour-cell fitness. Conversely, increasing the intracellular levels of succinate (a competitive inhibitor of αKG-dependent dioxygenases) blunts p53-driven tumour suppression. These data suggest that αKG is an effector of p53-mediated tumour suppression, and that the accumulation of αKG in p53-deficient tumours can drive tumour-cell differentiation and antagonize malignant progression.
AB - The tumour suppressor TP53 is mutated in the majority of human cancers, and in over 70% of pancreatic ductal adenocarcinoma (PDAC)1,2. Wild-type p53 accumulates in response to cellular stress, and regulates gene expression to alter cell fate and prevent tumour development2. Wild-type p53 is also known to modulate cellular metabolic pathways3, although p53-dependent metabolic alterations that constrain cancer progression remain poorly understood. Here we find that p53 remodels cancer-cell metabolism to enforce changes in chromatin and gene expression that favour a premalignant cell fate. Restoring p53 function in cancer cells derived from KRAS-mutant mouse models of PDAC leads to the accumulation of α-ketoglutarate (αKG, also known as 2-oxoglutarate), a metabolite that also serves as an obligate substrate for a subset of chromatin-modifying enzymes. p53 induces transcriptional programs that are characteristic of premalignant differentiation, and this effect can be partially recapitulated by the addition of cell-permeable αKG. Increased levels of the αKG-dependent chromatin modification 5-hydroxymethylcytosine (5hmC) accompany the tumour-cell differentiation that is triggered by p53, whereas decreased 5hmC characterizes the transition from premalignant to de-differentiated malignant lesions that is associated with mutations in Trp53. Enforcing the accumulation of αKG in p53-deficient PDAC cells through the inhibition of oxoglutarate dehydrogenase—an enzyme of the tricarboxylic acid cycle—specifically results in increased 5hmC, tumour-cell differentiation and decreased tumour-cell fitness. Conversely, increasing the intracellular levels of succinate (a competitive inhibitor of αKG-dependent dioxygenases) blunts p53-driven tumour suppression. These data suggest that αKG is an effector of p53-mediated tumour suppression, and that the accumulation of αKG in p53-deficient tumours can drive tumour-cell differentiation and antagonize malignant progression.
UR - http://www.scopus.com/inward/record.url?scp=85072686860&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072686860&partnerID=8YFLogxK
U2 - 10.1038/s41586-019-1577-5
DO - 10.1038/s41586-019-1577-5
M3 - Article
C2 - 31534224
AN - SCOPUS:85072686860
SN - 0028-0836
VL - 573
SP - 595
EP - 599
JO - Nature
JF - Nature
IS - 7775
ER -