Dual role of Sp3 transcription factor as an inducer of apoptosis and a marker of tumour aggressiveness.
BACKGROUND
The ambiguous role of transcription factor Sp3 for tumour progression is still debated since it was described as a transcriptional repressor or activator. Here we tried to decipher the molecular mechanisms implicated in Sp3 accumulation observed in aggressive tumours.


METHODS
We generated normal and tumour cell lines conditionally expressing Sp3. Cell growth was analyzed in vitro and after inoculation in nude mice. Apoptosis was assessed by pan- caspase activity assays, by counting fragmented nuclei and by determination of caspase 9 cleavage. Gene expression was determined by quantitative PCR. Cleavage by different caspases was performed after in vitro translation of the Sp3 cDNA in the presence of [S(35)] labelled methionine. Different tumour cell lines and head and neck tumour samples were tested for the presence of Sp3 by western blots. Correlation between Sp3 expression and overall survival has been statistically determined.


RESULTS
Conditional over-expression of Sp3 induces apoptosis and modifies expression of genes implicated in the regulation of cell cycle and pro and anti apoptotic genes. Sp3 over-expression strongly reduces the development of tumours in nude mice confirming its pro-apoptotic potential in vivo. However, cells can survive to apoptosis through selective Sp3 cleavage by caspase. Sp3 induction in established tumours resulted in transient regression then progression. Progression coincides with re-accumulation of the full length form of Sp3. Sp3 is over-expressed in tumour cell lines of different origins. The presence of high levels of the full-length form of Sp3 indicates a poor prognosis for overall survival of patients with head and neck tumours.


CONCLUSIONS
Full length Sp3 accumulation highlights bypass of tumour cell apoptotic capacities and is indicative of head and neck tumours aggressiveness.
Essafi-Benkhadir
Khadija
K
University of Nice-Sophia Antipolis, Institute of Developmental Biology and Cancer Research UMR CNRS 6543, Centre Antoine Lacassagne, Nice, France.
Grosso
Sébastien
S
Puissant
Alexandre
A
Robert
Guillaume
G
Essafi
Makram
M
Deckert
Marcel
M
Chamorey
Emmanuel
E
Dassonville
Olivier
O
Milano
Gérard
G
Auberger
Patrick
P
Pagès
Gilles
G
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011379:Prognosis; D051705:Sp3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate
D051705:Sp3 Transcription Factor; D020169:Caspases