FOXM1 expression mediates growth suppression during terminal differentiation of HO-1 human metastatic melanoma cells.
Induction of terminal differentiation represents a potentially less toxic cancer therapy. Treatment of HO-1 human metastatic melanoma cells with IFN-β plus mezerein (MEZ) promotes terminal differentiation with an irreversible loss of growth potential. During this process, the transcription factor FOXM1 is down-regulated potentially inhibiting transactivation of target genes including those involved in G(2)/M progression and cell proliferation. We investigated the mechanism of FOXM1 down-regulation and its physiological role in terminal differentiation. Genetic and pharmacological studies revealed that FOXM1 down-regulation was primarily caused by MEZ activation of PKCα and co-treatment with IFN-β plus MEZ augmented the effect of PKCα. Promoter analysis with a mutated E-box on the FOXM1 promoter, and in vitro and in vivo binding assays confirm a direct role of c-Myc on FOXM1 expression. Reduction of c-Myc and overexpression of Mad1 by IFN-β plus MEZ treatment should cause potent and persistent reduction of FOXM1 expression during terminal differentiation. Overexpression of FOXM1 restored expression of cell cycle-associated genes and increased the proportion of cells in the S phase. Our experiments support a model for terminal differentiation in which FOXM1 down-regulation via activation of PKCα followed by suppression of c-Myc expression, are causal events in promoting growth inhibition during terminal differentiation.
Huynh
Kim Mai
KM
Ilsong Institute of Life Science, Hallym University, Kyonggi-do, Republic of Korea.
Soh
Jae-Won
JW
Dash
Rupesh
R
Sarkar
Devanand
D
Fisher
Paul B
PB
Kang
Dongchul
D
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D000972:Antineoplastic Agents, Phytogenic; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004224:Diterpenes; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C079439:MXD1 protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; C011309:mezerein; D016899:Interferon-beta