KLF6-SV1 Is a Novel Antiapoptotic Protein That Targets the BH3-Only Protein NOXA for Degradation and Whose Inhibition Extends Survival in an Ovarian Cancer Model

DiFeo, Analisa; Huang, Fei; Sangodkar, Jaya; Terzo, Esteban A.; Leake, Devin; Narla, Goutham; Martignetti, John A.

doi:10.1158/0008-5472.can-08-4282

Cited by 38 publications

(49 citation statements)

References 46 publications

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“…The overall integrity of the mitochondrial function is controlled by the Bcl-2 family of proteins that includes both anti-apoptotic (Bcl-2, Bcl-XL, and Mcl-1) and proapoptotic members (Bax, Bak, Noxa, and p53 upregulated modulator of apoptosis (PUMA)) [31,32,[39][40][41]. Previous reports have demonstrated that the targeted reduction of KLF6-SV1 resulted in marked activation of the intrinsic pathway of apoptosis through upregulation of the pro-apoptotic Noxa and degradation of the anti-apoptotic Mcl-1 in lung, prostate, and ovarian cancer cell lines [10,24,26]. Here, we also confirmed that the expressions of Noxa and Mcl-1 could be regulated by KLF6-SV1 siRNA in gastric cancer cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…It was demonstrated that KLF6-SV1 was an important anti-apoptosis protein in some tumors [26]. (Fig.…”

Section: Klf6-sv1 Sirna Enhances the Apoptosis Of Gastric Cancer Cellsmentioning

confidence: 98%

“…To silence KLF6-SV1 expression, we selected a candidate sequence in the KLF6-SV1 cDNA for RNAi, as described previously [10,20,23,26]. The targeted KLF6-SV1 sequence was 5 0 -CAGGGAAGGAGAAAAGCCUUU-3 0 .…”

Section: Sirna Sequence and Constructmentioning

confidence: 99%

“…DNA amplification was carried out using Icycler (Bio-Rad, Hercules, CA, USA) and the detection was performed by measuring the binding of the fluorescence dye SYBR Green I to double-stranded DNA. All primer sequences and methods for quantifying KLF6 and KLF6-SV1 were performed as previously described [12,20,25,26]. All experiments were done in triplicate and independently validated three times.…”

Section: Real-time Quantitative Rt-pcr Analysismentioning

confidence: 99%

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A small interfering RNA targeting the KLF6 splice variant, KLF6-SV1, as gene therapy for gastric cancer

Chen

Sun

et al. 2011

Gastric Cancer

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Background Accumulating evidence suggests that the tumor suppressor gene Kruppel-like factor 6 (KLF6) and its dominant-negative splice form KLF6-SV1 play important roles in both the development and progression of cancer. However, the role of KLF6-SV1 in gastric cancer remains largely unknown. Methods KLF6-SV1 expression was detected in various human gastric cancer cell lines and gastric cancer patient samples by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting. Small interfering RNA (siRNA) was used to inhibit KLF6-SV1 expression in BGC-823 and SGC-7901 cell lines. The effects of downregulation of KLF6-SV1 by siRNA on cell proliferation, migration, invasion, and tumor growth were examined in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

“…It was demonstrated that KLF6-SV1 was an important anti-apoptosis protein in some tumors [26]. (Fig.…”

Section: Klf6-sv1 Sirna Enhances the Apoptosis Of Gastric Cancer Cellsmentioning

confidence: 98%

Section: Sirna Sequence and Constructmentioning

confidence: 99%

Section: Real-time Quantitative Rt-pcr Analysismentioning

confidence: 99%

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A small interfering RNA targeting the KLF6 splice variant, KLF6-SV1, as gene therapy for gastric cancer

Chen

Sun

et al. 2011

Gastric Cancer

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“…iv. Inhibition of KLF6-SV1 by RNAi in prostate carcinoma and ovarian cancer cell lines (41,47). v. Overexpression of KLF6-SV2 in immortalized human hepatocytes and HepG2 cell line (40).…”

Section: Klf6 Function In Cellmentioning

confidence: 99%

Biology of Krüppel‐like factor 6 transcriptional regulator in cell life and death

2010

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SummaryAn essential role for the Krü ppel-like transcription factor family has been determined in the regulation of remarkable processes including cell proliferation, differentiation, signal transduction, oncogenesis, and cell death. A member of this group, Krü ppel-like factor 6 (KLF6), identified on the basis of its ability to regulate a group of genes belonging to the carcinoembryonic antigen gene family, has been involved in human carcinogenesis. Early studies proposed a tumor suppressor function for KLF6 because of its ability to reduce cell proliferation through several biochemical mechanisms including regulation of cell cycle components, oncogene products, and apoptosis. Mutations within the klf6 gene, decreased expression and/or loss-of-heterozygosity were associated with the development of different human malignancies, and, hence, further supporting the tumor suppressor function of KLF6. This view has been challenged by other studies in distinct types of human cancers describing infrequent genetic alterations of klf6 gene or even enhanced expression in some tumors. The scenario about KLF6 function became still more complex as the description of oncogenic KLF6 splice variant 1 (SV1) with dominant negative activity against the wild type KLF6 (wtKLF6) protein. Additionally, increased evidence is suggesting that KLF6 is a bonafide target of several signaling cascades, which ultimate regulatory effect on this protein could drive decisions of cell life and death, facing the dilemma about how wtKLF6 could be involved in both processes. These apparently conflicting situations, emerged by apparently opposite effects mediated by wtKLF6, may be related, at least in part, to the biological cross-talk with the c-Jun oncoprotein. Depending on the stimulus received by the cell, wtKLF6 interaction with c-Jun determines different cell outcomes such as proliferation control or apoptosis. Thus, KLF6 responsiveness represents a kind of cell warning signal on receiving different stimuli, including oncogenic activation and microbial infections, orchestrating the implementation of proliferation and apoptotic programs.

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Enhanced hepatocarcinogenesis in mouse models and human hepatocellular carcinoma by coordinate KLF6 depletion and increased messenger RNA splicing

et al. 2012

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Background KLF6-SV1 (SV1), the major splice variant of KLF6, antagonizes the KLF6 tumor suppressor by an unknown mechanism. Decreased KLF6 expression in human hepatocellular carcinoma (HCC) correlates with increased mortality, but the contribution of increased SV1 is unknown. We sought to define the impact of SV1 on human outcomes and experimental murine hepatocarcinogenesis, and to elucidate its mechanism of action. Results In HCV-related HCC, an increased ratio of SV1/KLF6 within the tumor was associated with more features of more advanced disease. Six months after a single injection of diethylnitrosamine (DEN), SV1 hepatocyte transgenic mice developed more histologically advanced tumors, whereas Klf6-depleted mice developed bigger tumors compared to the Klf6fl(+/+) control mice. Nine months after DEN, SV1 transgenic-mice with Klf6-depletion had the greatest tumor burden. Primary mouse hepatocytes from both the SV1 transgenic animals and those with hepatocyte-specific Klf6 depletion displayed increased DNA synthesis, with an additive effect in hepatocytes harboring both SV1 over-expression and Klf6 depletion. Parallel results were obtained by viral SV1-transduction- and depletion of Klf6 through adenovirus-Cre infection of primary Klf6fl(+/+) hepatocytes. Increased DNA synthesis was due to both enhanced cell proliferation and increased ploidy. Co-IP studies in 293T cells uncovered a direct interaction of transfected SV1 with KLF6. Accelerated KLF6 degradation in the presence of SV1 was abrogated by the proteasome inhibitor MG132. Conclusion Increased SV1/KLF6 ratio correlates with more aggressive HCC. In mice, an increased SV1/KLF6 ratio, generated either by increasing SV1, decreasing KLF6, or both, accelerates hepatic carcinogenesis. Moreover, SV1 binds directly to KLF6 and accelerates its degradation. These findings represent a novel mechanism underlying the antagonism of tumor suppressor gene function by a splice variant of the same gene.

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KLF6-SV1 Is a Novel Antiapoptotic Protein That Targets the BH3-Only Protein NOXA for Degradation and Whose Inhibition Extends Survival in an Ovarian Cancer Model

Cited by 38 publications

References 46 publications

A small interfering RNA targeting the KLF6 splice variant, KLF6-SV1, as gene therapy for gastric cancer

A small interfering RNA targeting the KLF6 splice variant, KLF6-SV1, as gene therapy for gastric cancer

Biology of Krüppel‐like factor 6 transcriptional regulator in cell life and death

Enhanced hepatocarcinogenesis in mouse models and human hepatocellular carcinoma by coordinate KLF6 depletion and increased messenger RNA splicing

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