BibTex format
@article{Carrer:2019:10.1158/2159-8290.cd-18-0567,
author = {Carrer, A and Trefely, S and Zhao, S and Campbell, SL and Norgard, RJ and Schultz, KC and Sidoli, S and Parris, JLD and Affronti, HC and Sivanand, S and Egolf, S and Sela, Y and Trizzino, M and Gardini, A and Garcia, BA and Snyder, NW and Stanger, BZ and Wellen, KE},
doi = {10.1158/2159-8290.cd-18-0567},
journal = {Cancer Discovery},
pages = {416--435},
title = {Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis},
url = {http://dx.doi.org/10.1158/2159-8290.cd-18-0567},
volume = {9},
year = {2019}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, and new strategies for prevention and treatment are urgently needed. We previously reported that histone H4 acetylation is elevated in pancreatic acinar cells harboring Kras mutations prior to the appearance of premalignant lesions. Because acetyl-CoA abundance regulates global histone acetylation, we hypothesized that altered acetyl-CoA metabolism might contribute to metabolic or epigenetic alterations that promote tumorigenesis. We found that acetyl-CoA abundance is elevated in KRAS-mutant acinar cells and that its use in the mevalonate pathway supports acinar-to-ductal metaplasia (ADM). Pancreas-specific loss of the acetyl-CoA–producing enzyme ATP-citrate lyase (ACLY) accordingly suppresses ADM and tumor formation. In PDA cells, growth factors promote AKT–ACLY signaling and histone acetylation, and both cell proliferation and tumor growth can be suppressed by concurrent BET inhibition and statin treatment. Thus, KRAS-driven metabolic alterations promote acinar cell plasticity and tumor development, and targeting acetyl-CoA–dependent processes exerts anticancer effects.
AU - Carrer,A
AU - Trefely,S
AU - Zhao,S
AU - Campbell,SL
AU - Norgard,RJ
AU - Schultz,KC
AU - Sidoli,S
AU - Parris,JLD
AU - Affronti,HC
AU - Sivanand,S
AU - Egolf,S
AU - Sela,Y
AU - Trizzino,M
AU - Gardini,A
AU - Garcia,BA
AU - Snyder,NW
AU - Stanger,BZ
AU - Wellen,KE
DO - 10.1158/2159-8290.cd-18-0567
EP - 435
PY - 2019///
SN - 2159-8274
SP - 416
TI - Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis
T2 - Cancer Discovery
UR - http://dx.doi.org/10.1158/2159-8290.cd-18-0567
VL - 9
ER -