A functional family-wide screening of SP/KLF proteins identifies a subset of suppressors of KRAS-mediated cell growth

Abstract

SP/KLF transcription factors comprise an emerging group of proteins that may behave as tumor suppressors. Incidentally, many cancers displaying alterations in certain KLF proteins are also associated with a high incidence of KRAS mutations. Therefore, we here 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 discover 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 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 colonies in soft agar and tumor 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 cell cycle arrest in S phase. Interestingly, similar to KLF11, KLF14 and KLF16 mechanistically share the ability to modulate the expression of cyclin A. Collectively, this study stringently defines a distinct subset of SP/KLF proteins that impairs KRAS-mediated cell growth, and that mechanistically, some members of this subset accomplish this, at least in part, through regulation of the cyclin A promoter.

Long Noncoding RNA ANRIL Promotes Non–Small Cell Lung Cancer Cell Proliferation and Inhibits Apoptosis by Silencing KLF2 and P21 Expression

“…Some KLF members are emerging as tumor-suppressor genes due to their roles in the inhibition of proliferation, migration, and induction of apoptosis (30,31). KLF2, as a member of KLF family, is diminished in many cancers and possesses tumor-suppressor features such as inhibition of cell proliferation mediated by KRAS (32)(33)(34). Moreover, there is evidence that showed that EZH2 could silence KLF2 expression and block the tumor-suppressor features of KLF2, which is partly mediated by p21 (21).…”

Krüppel-like factor 14 increases insulin sensitivity through activation of PI3K/Akt signal pathway

“…KLF14 belongs to the SP/KLF (Specificity protein/Krüppel-like factor) family which constitutes a group of transcription factors that are present in organisms ranging from yeast to vertebrates [22,23]. KLF14 is also characterized by the presence of three highly conserved C-terminal Cys2His2 zinc finger domains responsible for DNA binding and regulates the transcription of various genes.…”

Influence of different hypoxia types on p-glycoprotein functional activity and expression

“…Представители семейства Sp-белков (называемые также krüppel-like factors -KLF) связы-ваются с так называемыми Sp1-сайтами (GC-бокс, GT-бокс, CACCC-бокс) промоторов или энхансеров различных генов и регулируют их экспрессию, уча-ствуя в клеточной пролиферации, ангиогенезе, апоп-тозе и опухолевой прогрессии. Их молекулы вклю-чают три высококонсервативных ДНК-связывающих домена (65 % сходства нуклеотидной последова-тельности у различных членов семейства), каждый из которых формирует структуру типа «цинковый палец» на С-конце и способствует связыванию транскрипционного фактора с соответствующими участками генома и межбелковым взаимодействи-ям, вариантный N-концевой домен, ответственный за трансактивационную или ингибирующую актив-ность и способность связываться с корепрессорами и коактиваторами, а также структуру, регулирую-щую ядерную локализацию фактора [10, 15,18,22]. В активации и ингибировании экспрессии генов под влиянием членов Sp1/KLF-семейства ведущая роль отводится деацетилированию и ацетилированию ги-стонов [18].…”