Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-XL, c-Jun, and p21CIP1, but independent of p53

Oncogene. 1999 Nov 25;18(50):7016-25. doi: 10.1038/sj.onc.1203176.


Determinants of differentiation and apoptosis in myelomonocytic leukemia cells (U937) exposed to the novel hybrid polar compound SAHA (suberoylanilide hydroxamic acid) have been examined. In contrast to hexamethylenbisacetamide (HMBA), SAHA-related maturation was limited and accompanied by marked cytoxicity. SAHA-mediated apoptosis occurred within the G0G1 and S phase populations, and was associated with decreased mitochondrial membrane potential, caspase-3 activation, PARP degradation, hypophosphorylation/cleavage of pRB, and down-regulation of c-Myc, c-Myb, and B-Myb. Enforced expression of Bcl-2 or Bcl-XL inhibited SAHA-induced apoptosis, but only modestly potentiated differentiation. While SAHA induced the cyclin-dependent kinase inhibitor p21CIP1, antisense ablation of this CDKI increased, rather than decreased, SAHA-related lethality. In contrast, conditional expression of wild-type p53 failed to modify SAHA actions, but markedly potentiated HMBA-induced apoptosis. Finally, SAHA modestly increased expression/activation of the stress-activated protein kinase (SAPK/JNK); moreover, SAHA-related lethality was partially attenuated by a dominant-negative c-Jun mutant protein (TAM67). SAHA did not stimulate mitogen-activated protein kinase (MAPK), nor was lethality diminished by the specific MEK/MAPK inhibitor PD98059. These findings indicate that SAHA potently induces apoptosis in human leukemia cells via a pathway that is p53-independent but at least partially regulated by Bcl-2/Bcl-XL, p21CIP1, and the c-Jun/AP-1 signaling cascade.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis / drug effects*
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / metabolism*
  • Down-Regulation
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Leukemia / metabolism
  • Leukemia / pathology
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Proto-Oncogene Proteins c-myb / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • U937 Cells
  • Vorinostat
  • bcl-X Protein


  • BCL2L1 protein, human
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Hydroxamic Acids
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-jun
  • Proto-Oncogene Proteins c-myb
  • Proto-Oncogene Proteins c-myc
  • Tumor Suppressor Protein p53
  • bcl-X Protein
  • Vorinostat