TY - JOUR
T1 - Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis
AU - Diesch, Jeannine
AU - Le Pannérer, Marguerite Marie
AU - Winkler, René
AU - Casquero, Raquel
AU - Muhar, Matthias
AU - van der Garde, Mark
AU - Maher, Michael
AU - Herráez, Carolina Martínez
AU - Bech-Serra, Joan J.
AU - Fellner, Michaela
AU - Rathert, Philipp
AU - Brooks, Nigel
AU - Zamora, Lurdes
AU - Gentilella, Antonio
AU - de la Torre, Carolina
AU - Zuber, Johannes
AU - Götze, Katharina S.
AU - Buschbeck, Marcus
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - The nucleotide analogue azacitidine (AZA) is currently the best treatment option for patients with high-risk myelodysplastic syndromes (MDS). However, only half of treated patients respond and of these almost all eventually relapse. New treatment options are urgently needed to improve the clinical management of these patients. Here, we perform a loss-of-function shRNA screen and identify the histone acetyl transferase and transcriptional co-activator, CREB binding protein (CBP), as a major regulator of AZA sensitivity. Compounds inhibiting the activity of CBP and the closely related p300 synergistically reduce viability of MDS-derived AML cell lines when combined with AZA. Importantly, this effect is specific for the RNA-dependent functions of AZA and not observed with the related compound decitabine that is only incorporated into DNA. The identification of immediate target genes leads us to the unexpected finding that the effect of CBP/p300 inhibition is mediated by globally down regulating protein synthesis.
AB - The nucleotide analogue azacitidine (AZA) is currently the best treatment option for patients with high-risk myelodysplastic syndromes (MDS). However, only half of treated patients respond and of these almost all eventually relapse. New treatment options are urgently needed to improve the clinical management of these patients. Here, we perform a loss-of-function shRNA screen and identify the histone acetyl transferase and transcriptional co-activator, CREB binding protein (CBP), as a major regulator of AZA sensitivity. Compounds inhibiting the activity of CBP and the closely related p300 synergistically reduce viability of MDS-derived AML cell lines when combined with AZA. Importantly, this effect is specific for the RNA-dependent functions of AZA and not observed with the related compound decitabine that is only incorporated into DNA. The identification of immediate target genes leads us to the unexpected finding that the effect of CBP/p300 inhibition is mediated by globally down regulating protein synthesis.
UR - http://www.scopus.com/inward/record.url?scp=85117496098&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-26258-z
DO - 10.1038/s41467-021-26258-z
M3 - Article
C2 - 34663789
AN - SCOPUS:85117496098
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6060
ER -