15-LOX-1 transcription suppression through the NuRD complex in colon cancer cells.
15-Lipoxygenase-1 (15-LOX-1) is transcriptionally silenced in cancer cells, and its transcription reactivation (for example, through histone deacetylase inhibitors (HDACIs)) restores apoptosis to cancer cells. However, the exact mechanism underlying 15-LOX-1 transcription reactivation in cancer cells is still undefined. Therefore, we evaluated the critical mechanisms required for 15-LOX-1 transcription reactivation in colon cancer cells. Specific HDAC1 and HDAC2 inhibition activated 15-LOX-1 transcription. 15-LOX-1 transcription was repressed through transcription repressor complex recruitment in the region of -120 to -391 of the 15-LOX-1 promoter. The nucleosome remodeling and histone deacetylase (NuRD) repression complex was recruited to this region. Depsipeptide significantly reduced the recruitment of NuRD key components (for example, metastasis-associated protein 1 (MTA1) and HDAC1) to the 15-LOX-1 promoter before 15-LOX-1 transcriptional activation. Knock down of NuRD key components (for example, MTA1 and HDAC1) by small interfering RNA (siRNA) activated 15-LOX-1 transcription, as measured by luciferase reporter assays in stably transfected SW480 cells with the 15-LOX-1 promoter construct of the -391, but not the -120 region. Relative to expression in normal tissue, MTA1 expression in colorectal cancer mucosa from colorectal cancer patients was negatively related to 15-LOX-1 expression. Thus, our results show that NuRD contributes to 15-LOX-1 transcription suppression in colon cancer cells and that HDACIs can inhibit NuRD recruitment to a promoter to activate gene transcription, as in the case of 15-LOX-1.
Zuo
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Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
Morris
J S
JS
Broaddus
R
R
Shureiqi
I
I
D000368:Aged; D000369:Aged, 80 and over; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology; D005260:Female; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators; D014158:Transcription, Genetic
D056572:Histone Deacetylase Inhibitors; C089320:MTA1 protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; D001093:Arachidonate 15-Lipoxygenase; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex