KLF4 Is Essential for Induction of Cellular Identity Change and Acinar-to-Ductal Reprogramming during Early Pancreatic Carcinogenesis

Wei, Daoyan; Wang, Liang; Yan, Yongmin; Jia, Zhiliang; Gagea, Mihai; Li, Zhiwei; Zuo, Xiangsheng; Kong, Xiangyu; Huang, Suyun; Xie, Keping

doi:10.1016/j.ccell.2016.02.005

Cited by 132 publications

(121 citation statements)

References 62 publications

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“…Although the relationship between ER stress and ADM is not well understood, a recent report suggests that ER stress resulting from perturbation of basal autophagy via loss of ATG7 is associated with spontaneous activation of ADM in a mouse model (42). ADM is critical for the initiation of pancreatic tumorigenesis (5,32). In the PKC acinar cells, GRP78 was highly elevated, suggesting that it could play a role in ADM under oncogenic stress.…”

Section: Discussionmentioning

confidence: 99%

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

Shen

Zhu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease in critical need of new therapeutic strategies. Here, we report that the stress-inducible 78-kDa glucose-regulated protein (GRP78/HSPA5), a key regulator of endoplasmic reticulum homeostasis and PI3K/AKT signaling, is overexpressed in the acini and PDAC of Pdx1-Cre;Kras G12D/+ ;p53 f/+ (PKC) mice as early as 2 mo, suggesting that GRP78 could exert a protective effect on acinar cells under stress, as during PDAC development. The PKC pancreata bearing wild-type Grp78 showed detectable PDAC by 3 mo and rapid subsequent tumor growth. In contrast, the PKC pancreata bearing a Grp78 f/+ allele (PKC78 f/+ mice) expressing about 50% of GRP78 maintained normal sizes during the early months, with reduced proliferation and suppression of AKT, S6, ERK, and STAT3 activation. Acinar-to-ductal metaplasia (ADM) has been identified as a key tumor initiation mechanism of PDAC. Compared with PKC, the PKC78 f/+ pancreata showed substantial reduction of ADM as well as pancreatic intraepithelial neoplasia-1 (PanIN-1), PanIN-2, and PanIN-3 and delayed onset of PDAC. ADM in response to transforming growth factor α was also suppressed in ex vivo cultures of acinar cell clusters isolated from mouse pancreas bearing targeted heterozygous knockout of Grp78 (c78 f/+ ) and subjected to 3D culture in collagen. We further discovered that GRP78 haploinsufficiency in both the PKC78 f/+ and c78 f/+ pancreata leads to reduction of epidermal growth factor receptor, which is critical for ADM initiation. Collectively, our studies establish a role for GRP78 in ADM and PDAC development.glucose-regulated protein 78 | GRP78 | pancreatic ductal adenocarcinoma | acinar-to-ductal metaplasia | Kras P ancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest diseases with limited therapeutic options and an overall 5-y survival rate of <10%; therefore, identification of targetable key players in tumor initiation as well as tumor maintenance is urgently needed (1). PDAC is believed to arise from a range of preneoplastic mucinous lesions with ductal morphology, pancreatic intraepithelial neoplasia (PanIN) being the most common in humans (2). About 90% of PDAC contains activating mutations of KRAS whereas 50-75% contain mutations in Tp53 (1). Mutationally activated oncogenic KRAS signals through the PI3K-PDK1-AKT pathway and the canonical mitogen-activated protein kinase pathway via RAF-MEK1/2-ERK1/2, as well as via positive feedback activation of receptor tyrosine kinases engaged by autocrine and paracrine stimuli (3). Although the histological appearance of PDAC suggests a ductal cell of origin, accumulating evidence reveals that PDAC originates primarily through transdifferentiation of acinar cells into ductal cells in a process referred to as acinar-to-ductal metaplasia (ADM), although centroacinar cells and pancreas precursor cells could also give rise to PDAC (2, 4, 5). To study PDAC, a pancreatic cancer mouse model mimicking human PDAC has been established using the pancreatic...

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Section: Discussionmentioning

confidence: 99%

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

Shen

Zhu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Conflicting evidences surprisingly uncovered the fact that KLF4 may have an ambivalent role in tumorigenesis in a tissue-specific manner. Actually, KLF4 acts as a tumor suppressor in colon, 13 gastric, 14 esophageal, 15,16 bladder 17 and lung cancer, 18 whereas in pancreatic 19 and breast cancer, 20,21 KLF4 is believed to function as an oncogene. For example, KLF4 is a key regulator in the initiation of premalignant intraepithelial neoplasia by mutant Kras in pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

“…For example, KLF4 is a key regulator in the initiation of premalignant intraepithelial neoplasia by mutant Kras in pancreatic cancer. 19 Owing to its importance in physiological and pathological processes, KLF4 is critically regulated on different levels. Studies in recent years gradually unveiled the underlying mechanism of KLF4 regulation.…”

Section: Introductionmentioning

confidence: 99%

FBXO32 suppresses breast cancer tumorigenesis through targeting KLF4 to proteasomal degradation

et al. 2017

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Krüppel-like factor 4 (KLF4, GKLF) is a zinc-finger transcription factor involved in a large variety of cellular processes, including apoptosis, cell cycle progression, as well as stem cell renewal. KLF4 is critical for cell fate decision and has an ambivalent role in tumorigenesis. Emerging data keep reminding us that KLF4 dysregulation either facilitates or impedes tumor progression, making it important to clarify the regulating network of KLF4. Like most transcription factors, KLF4 has a rather short half-life within the cell and its turnover must be carefully orchestrated by ubiquitination and ubiquitin–proteasome system. To better understand the mechanism of KLF4 ubiquitination, we performed a genome-wide screen of E3 ligase small interfering RNA library based on western blot and identified SCF-FBXO32 to be a new E3 ligase, which is responsible for KLF4 ubiquitination and degradation. The F-box domain is critical for FBXO32-dependent KLF4 ubiquitination and degradation. Furthermore, we demonstrated that FBXO32 physically interacts with the N-terminus (1–60 aa) of KLF4 via its C-terminus (228–355 aa) and directly targets KLF4 for ubiquitination and degradation. We also found out that p38 mitogen-activated protein kinase pathway may be implicated in FBXO32-mediated ubiquitination of KLF4, as p38 kinase inhibitor coincidently abrogates endogenous KLF4 ubiquitination and degradation, as well as FBXO32-dependent exogenous KLF4 ubiquitination and degradation. Finally, FBXO32 inhibits colony formation in vitro and primary tumor initiation and growth in vivo through targeting KLF4 into degradation. Our findings thus further elucidate the tumor-suppressive function of FBXO32 in breast cancer. These results expand our understanding of the posttranslational modification of KLF4 and of its role in breast cancer development and provide a potential target for diagnosis and therapeutic treatment of breast cancer.

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“…Lo et al [6] reported that the expression of underglycosylated mucin 1 antigen varied from the PanIN stage to the late stages of the disease. Krüppel-like factor 4 is upregulated in PanIN and is essential for acinar-to-ductal metaplasia in the early stage of pancreatic carcinogenesis [7].…”

Section: Introductionmentioning

confidence: 99%

miRNA-1290 Promotes Aggressiveness in Pancreatic Ductal Adenocarcinoma by Targeting IKK1

Huang

Zheng

et al. 2018

Cell Physiol Biochem

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Background/Aims: MicroRNAs (miRNAs) are a group of non-coding RNAs that play diverse roles in pancreatic carcinogenesis. In pancreatic ductal adenocarcinoma (PDAC), NF-kB is constitutively activated in most patients and is linked to a mutation in KRAS via IkB kinase complex 1 (IKK1, also known as IKKa). We investigated the link between PDAC aggressiveness and miR-1290. Methods: We used miRCURY^TM LNA Array and in situ hybridization to investigate candidate miRNAs and validated the findings with PCR. The malignant behavior of cell lines was assessed with Cell Counting Kit-8, colony formation, and Transwell assays. A dual-luciferase reporter assay was used to evaluate the interaction between miR-1290 and IKK1. Protein expression was observed by western blotting. Results: In this study, 36 miRNAs were dysregulated in high-grade pancreatic intraepithelial neoplasia (PanIN) and PDAC tissues compared with low-grade PanIN tissues. The area under the curve values of miR-1290 and miR-31-5p were 0.829 and 0.848, respectively (95% confidence interval, 0.722–0.936 and 0.749–0.948, both P < 0.001). There was a significant correlation between miR-1290 and histological differentiation (P = 0.029), pT stage (P = 0.006), and lymph node metastasis (P = 0.001). In addition, the in vitro work showed that miR-1290 promoted PDAC cell proliferation, invasion, and migration. Western blotting and the dual-luciferase reporter assay showed that miR-1290 promoted cancer aggressiveness by directly targeting IKK1. The synergist effect of miR-1290 on the proliferation and metastasis of PDAC cells was attenuated and enhanced by IKK1 overexpression and knockdown, respectively. Consistent with the in vitro results, a subcutaneous tumor mouse model showed that miR-1290 functioned as a potent promoter of PDAC in vivo. Conclusion: MiR-1290 may act as an oncogene by directly targeting the 3’-untranslated region of IKK1, and the miR-1290/IKK1 pathway may prove to be a novel diagnostic and therapeutic target for PDAC.

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KLF4 Is Essential for Induction of Cellular Identity Change and Acinar-to-Ductal Reprogramming during Early Pancreatic Carcinogenesis

Cited by 132 publications

References 62 publications

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

FBXO32 suppresses breast cancer tumorigenesis through targeting KLF4 to proteasomal degradation

miRNA-1290 Promotes Aggressiveness in Pancreatic Ductal Adenocarcinoma by Targeting IKK1

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