TY - JOUR
T1 - A functional family-wide screening of SP/KLF proteins identifies a subset of suppressors of KRAS-mediated cell growth
AU - Fernandez-Zapico, Martin E.
AU - Lomberk, Gwen A.
AU - Tsuji, Shoichiro
AU - DeMars, Cathrine J.
AU - Bardsley, Michael R.
AU - Lin, Yi Hui
AU - Almada, Luciana L.
AU - Han, Jing Jing
AU - Mukhopadhyay, Debabrata
AU - Ordog, Tamas
AU - Buttar, Navtej S.
AU - Urrutia, Raul
PY - 2011/4/15
Y1 - 2011/4/15
N2 - SP/KLF (Specificity protein/Krüppel-like factor) transcription factors comprise an emerging group of proteins that may behave as tumour suppressors. Incidentally, many cancers that display alterations in certain KLF proteins are also associated with a high incidence of KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue) mutations. Therefore in the present paper we investigate whether SP/KLF proteins suppress KRAS-mediated cell growth, and more importantly, the potential mechanisms underlying these effects. Using a comprehensive family-wide screening of the 24 SP/KLF members, we discovered that SP5, SP8, KLF2, KLF3, KLF4, KLF11, KLF13, KLF14, KLF15 and KLF16 inhibit cellular growth and suppress transformation mediated by oncogenic KRAS. Each protein in this subset of SP/KLF members individually inhibits BrdU (5-bromo-2-deoxyuridine) incorporation in KRAS oncogenic-mutant cancer cells. SP5, KLF3, KLF11, KLF13, KLF14 and KLF16 also increase apoptosis in these cells. Using KLF11 as a representative model for mechanistic studies, we demonstrate that this protein inhibits the ability of cancer cells to form both colonies in soft agar and tumour growth in vivo. Molecular studies demonstrate that these effects of KLF11 are mediated, at least in part, through silencing cyclin A via binding to its promoter and leading to cellcycle arrest in S-phase. Interestingly, similar to KLF11, KLF14 and KLF16 mechanistically share the ability to modulate the expression of cyclin A. Collectively, the present study stringently defines a distinct subset of SP/KLF proteins that impairs KRASmediated cell growth, and that mechanistically some members of this subset accomplish this, at least in part, through regulation of the cyclin A promoter.
AB - SP/KLF (Specificity protein/Krüppel-like factor) transcription factors comprise an emerging group of proteins that may behave as tumour suppressors. Incidentally, many cancers that display alterations in certain KLF proteins are also associated with a high incidence of KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue) mutations. Therefore in the present paper we investigate whether SP/KLF proteins suppress KRAS-mediated cell growth, and more importantly, the potential mechanisms underlying these effects. Using a comprehensive family-wide screening of the 24 SP/KLF members, we discovered that SP5, SP8, KLF2, KLF3, KLF4, KLF11, KLF13, KLF14, KLF15 and KLF16 inhibit cellular growth and suppress transformation mediated by oncogenic KRAS. Each protein in this subset of SP/KLF members individually inhibits BrdU (5-bromo-2-deoxyuridine) incorporation in KRAS oncogenic-mutant cancer cells. SP5, KLF3, KLF11, KLF13, KLF14 and KLF16 also increase apoptosis in these cells. Using KLF11 as a representative model for mechanistic studies, we demonstrate that this protein inhibits the ability of cancer cells to form both colonies in soft agar and tumour growth in vivo. Molecular studies demonstrate that these effects of KLF11 are mediated, at least in part, through silencing cyclin A via binding to its promoter and leading to cellcycle arrest in S-phase. Interestingly, similar to KLF11, KLF14 and KLF16 mechanistically share the ability to modulate the expression of cyclin A. Collectively, the present study stringently defines a distinct subset of SP/KLF proteins that impairs KRASmediated cell growth, and that mechanistically some members of this subset accomplish this, at least in part, through regulation of the cyclin A promoter.
KW - Cyclin A
KW - Krüppel-like factor (KLF) protein
KW - Krüppel-like factor 11 (KLF11)
KW - Pancreatic cancer
KW - Tumour suppression
KW - V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS)
UR - http://www.scopus.com/inward/record.url?scp=79953172903&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79953172903&partnerID=8YFLogxK
U2 - 10.1042/BJ20100773
DO - 10.1042/BJ20100773
M3 - Article
C2 - 21171965
AN - SCOPUS:79953172903
SN - 0264-6021
VL - 435
SP - 529
EP - 537
JO - Biochemical Journal
JF - Biochemical Journal
IS - 2
ER -