Polo-like kinase 1 expression is suppressed by CCAAT/enhancer-binding protein α to mediate colon carcinoma cell differentiation and apoptosis.
Human polo-like kinase 1 (PLK1), a highly conserved serine/threonine kinase is a key player in several essential cell-cycle events. PLK1 is considered an oncogene and its overexpression often correlates with poor prognosis of cancers, including colorectal cancer (CRC). However, regulation of PLK1 expression in colorectal cells was never studied earlier and it is currently unknown if PLK1 regulates differentiation and apoptosis of CRC.



PLK1 expression was analyzed by real-time PCR and western blotting. Transcriptional regulation was studied by reporter assay, gene knock-down, EMSA and ChIP.



PLK1 expression was down-regulated during butyrate-induced differentiation of HT-29 and other CRC cells. Also, PLK1 down-regulation mediated the role of butyrate in CRC differentiation and apoptosis. We report here a novel transcriptional regulation of PLK1 by butyrate. Transcription factors CCAAT/enhancer-binding protein α (C/EBPα) and Oct-1 share an overlapping binding site over the PLK1 promoter. Elevated levels of C/EBPα by butyrate treatment of CRC cells competed out the activator protein Oct-1 from binding to the PLK1 promoter and sequestered it. Binding of C/EBPα was associated with increased deacetylation near the transcription start site (TSS) of the PLK1 promoter, which abrogated transcription through reduced recruitment of RNA polymerase II. We also found a synergistic role between the synthetic PLK1-inhibitor SBE13 and butyrate on the apoptosis of CRC cells.



This study offered a novel p53-independent regulation of PLK1 during CRC differentiation and apoptosis.



Down-regulation of PLK1 is one of the mechanisms underlying the anti-cancer role of dietary fibre-derived butyrate in CRC.
National Institute of Cholera & Enteric Diseases (ICMR), Clinical Medicine, P-33, CIT Road, Scheme-XM, Beliaghata, Kolkata 700010, West Bengal, India; Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Road, La Jolla, CA 92037, United States.
Nirmalya
N
Dasgupta
National Institute of Cholera & Enteric Diseases (ICMR), Clinical Medicine, P-33, CIT Road, Scheme-XM, Beliaghata, Kolkata 700010, West Bengal, India.
Bhupesh Kumar
BK
Thakur
National Institute of Cholera & Enteric Diseases (ICMR), Clinical Medicine, P-33, CIT Road, Scheme-XM, Beliaghata, Kolkata 700010, West Bengal, India.
Atri
A
Ta
National Institute of Cholera & Enteric Diseases (ICMR), Clinical Medicine, P-33, CIT Road, Scheme-XM, Beliaghata, Kolkata 700010, West Bengal, India.
Sayan
S
Das
BD Biosciences, Salt Lake, Kolkata 700102, India.
George
G
Banik
National Institute of Cholera & Enteric Diseases (ICMR), Clinical Medicine, P-33, CIT Road, Scheme-XM, Beliaghata, Kolkata 700010, West Bengal, India. Electronic address: santasabujdas@yahoo.com.
Santasabuj
S
Das
D017209:Apoptosis / Q000187:drug effects; D001596:Benzylamines / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D050811:Octamer Transcription Factor-1 / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D011725:Pyridines / Q000494:pharmacology; D000097869:Polo-Like Kinase 1
D001596:Benzylamines; D002087:Butyrates; D022763:CCAAT-Enhancer-Binding Protein-alpha; D018797:Cell Cycle Proteins; D050811:Octamer Transcription Factor-1; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D000097869:Polo-Like Kinase 1; C549033:SBE13 compound
C/EBPα; Colorectal cancer; Polo-like kinase 1; SBE13; Sodium butyrate