Cilia loss sensitizes cells to transformation by activating the mevalonate pathway

Deng, Yue; Zhang, Cai; Shi, Shuo; Jiang, Hao; Shang, Yu; Ma, Ning; Wang, Jing Jing; Guan, Dong Xian; Chen, Tian Wei; Rong, Ye; Qian, Zhen; Zhang, Er Bin; Feng, Dan; Zhou, Quan; Du, Yi; Liu, Dong Ping; Huang, Xing Xu; Liu, Luming; Chin, Eugene; Li, Dang Sheng; Wang, Xiao Fan; Zhang, Xue Li; Xie, Dong

doi:10.1084/jem.20170399

Cited by 47 publications

(50 citation statements)

References 42 publications

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“…Seeley el al investigated oncogenic Kras‐driven mouse models for pancreatic cancer displaying a down‐regulation of PC during the transition from normal pancreas tissue to precursor lesions. Tissue‐specific knockdown of PC in this mouse model was found in another study to promote tumor formation by activating the mevalonate pathway . The work of Seeley et al also described the absence of PC in precursor lesions of patients and concluded that the down‐regulation of PC is an early event in pancreatic carcinogenesis.…”

Section: Pc In Epithelial Cancersmentioning

confidence: 56%

Mixed signals from the cell's antennae: primary cilia in cancer

Eguether

Hahne

2018

EMBO Reports

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Primary cilia (PC) are antenna‐like organelles that protrude from most mammalian cells. They are essential for the regulation of several signaling pathways such as Hedgehog and WNT. It is therefore not surprising that a dysfunction of PC is frequently associated with pathologies. Originally, PC were found to be involved in a variety of diseases commonly referred to as ciliopathies including cystic kidney diseases. Evidence is accumulating that PC play also an important role in cancer formation and regulation, which is the focus of this review.

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Section: Pc In Epithelial Cancersmentioning

confidence: 56%

Mixed signals from the cell's antennae: primary cilia in cancer

Eguether

Hahne

2018

EMBO Reports

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“…These genes were cloned into the p23/pLKO.1 vectors or for transient (using the Lipofectamine 2000 according to the manufacturer's instructions; Thermo Fisher Scientific, Waltham, MA, USA) or stable expression in 7404 or Huh‐7 cells. The lentivirus was used to produce the stable transformants.…”

Section: Methodsmentioning

confidence: 99%

“…and Gli1 (NM_005269.3) were amplified from reverse-transcribed cDNA from HEK293T cells (KLF2: forward, 5′-ATGGCGCTGAG TGAACCCATCC-3′; reverse, 5′-CTACATGTGCCGTTTCATGT-3′; HDA C1: forward, 5′-ATGGCGCAGACGCAGGGCACCCG-3′; reverse, 5′-TC AGGCCAACTTGACCTCCT-3′; and Gli1: forward, 5′-ATGTTCA ACTCGATGACCCC-3′; reverse, 5′-TTAGGCACTAGAGTTGAGGAA-3′) and then were cloned into P23, pcDNA3.1 and pCMV-HA vectors, respectively, to obtain the Flag, myc and HA tag. Plasmids were sequenced at Sangon Biotech (Shanghai, China) to confirm the sequence accuracy.These genes were cloned into the p2329 /pLKO.1 30 vectors or for transient (using the Lipofectamine 2000 according to the manufacturer's instructions; Thermo Fisher Scientific, Waltham, MA, USA) or stable expression in 7404 or Huh-7 cells. The lentivirus was used to produce the stable transformants.…”

mentioning

confidence: 99%

Krüppel‐like factor 2 inhibits hepatocarcinogenesis through negative regulation of the Hedgehog pathway

Lin

Nie

et al. 2019

Cancer Science

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Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The most important reason for the occurrence of HCC is hepatitis C or B infection. Moreover, genetic factors play an important role in the tumorigenesis of HCC. Here, we demonstrated that Krüppel‐like factor 2 (KLF2) expression was downregulated in HCC samples compared with adjacent tissues. Additionally, KLF2 was shown to inhibit the growth, migration and colony‐formation ability of liver cancer cells. Further mechanistic studies revealed that KLF2 can compete with Gli1 for interaction with HDAC1 and restrains Hedgehog signal activation. Together, our results suggest that KLF2 has potential as a diagnostic biomarker and therapeutic target for the treatment of HCC.

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“…Unlike the motile cilia, the primary cilia are microtubule‐based organelles located at the cytomembrane that act as sensors to receive physical and chemical signals . In the past ten years, this largely ignored organelle has been brought to the forefront of cancer research . Loss of cilia was observed in various cancer cells and gradually regarded as a common hallmark of the disease .…”

Section: Introductionmentioning

confidence: 99%

“…9 In the past ten years, this largely ignored organelle has been brought to the forefront of cancer research. [9][10][11][12] Loss of cilia was observed in various cancer cells and gradually regarded as a common hallmark of the disease. 9,[11][12][13] Restoring the expression of primary cilia appears to be a promising therapeutic method for cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

The association between methylation patterns of DNAH17 and clinicopathological factors in hepatocellular carcinoma

et al. 2018

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BackgroundHepatocellular carcinoma (HCC) is a malignancy with poor prognosis. Complex genetic and epigenetic alterations are the two primary causes of HCC. The aim of the study was mainly to explore the correlation between the methylation status of DNAH17 and HCC.MethodsWe evaluated the methylation levels of DNAH17 in 163 HCC samples and their paired normal tissue using Sequenom EpiTYPER assays and performed the TaqMan copy number assay to assess the copy number status of DNAH17 in HCC samples.ResultsThe mean methylation levels were significantly decreased in the tumor tissues compared to the paired normal tissues in both selected regions of DNAH17 (amplicon 1:58.7% vs 84.5%, P < 0.0001; amplicon 2:69.9% vs 84.5%, P = 0.0060). Contrarily，both RNA‐seq and immunohistochemistry indicated the expression of DNAH17 was increased in tumor tissues (P < 0.05). DNMT inhibitor decitabine treatment could increase the expression of DNAH17 in HCC cell lines. DNAH17 gene amplification always companied with hypomethylation status. Moreover, hypomethylation status was associated with several clinical characteristics, such as male patients, higher AFP values, higher age of onset, fibrous capsules, tumor necrosis, liver cirrhosis, and tumor thrombus (P < 0.05). Receiver operator characteristic (ROC) curve analysis demonstrated the methylation levels of DNAH17 could efficiently predict the existence of the fibrous capsule (AUC = 0.695) and tumor thrombus (AUC = 0.806).ConclusionsThese findings suggested that aberrant methylation of DNAH17 was associated with comprehensive HCC clinicopathological factors and could be a promising biomarker for tumor thrombosis in HCC patients.

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Cilia loss sensitizes cells to transformation by activating the mevalonate pathway

Abstract: Cilia loss is common in cancer, and its roles remain unknown. Deng et al. show that cilia loss sensitizes cells to transformation by activating a mevalonate pathway through β-catenin–TCF signaling. The mevalonate pathway inhibitor statin blocks the progression of pancreatic cancer.

Cited by 47 publications

References 42 publications

Mixed signals from the cell's antennae: primary cilia in cancer

Mixed signals from the cell's antennae: primary cilia in cancer

Krüppel‐like factor 2 inhibits hepatocarcinogenesis through negative regulation of the Hedgehog pathway

The association between methylation patterns of DNAH17 and clinicopathological factors in hepatocellular carcinoma

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