CHD1L promotes lineage reversion of hepatocellular carcinoma through opening chromatin for key developmental transcription factors

Liu, Ming; Chen, Leilei; Ma, Ning‐Fang; Chow, Raymond Kwok Kei; Li, Yan; Song, Yangyang; Chan, Tim; Fang, Shuo; Yang, Xiaodong; Xi, Shaoyan; Jiang, Lingxi; Li, Yun; Zeng, Tingting; Yuan, Yufeng; Guan, Xin‐Yuan

doi:10.1002/hep.28437

Cited by 30 publications

(16 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our analysis also identifies how the oncogene ALC1 might be targeted in cancer. Small molecules that inhibit its allostery or activity should reproduce ALC1 knockdown phenotypes, such as reduced tumor growth, reduced reprogramming, and increased sensitivity to chemotherapy (Jiang et al, 2015;Liu et al, 2016). Compounds that stabilize the inactive, gated conformation of ALC1, which lower its catalytic activity, or that disrupt its ability to recognize PAR should suppress the potent chromatin relaxation activity of this oncogene.…”

Section: Discussionmentioning

confidence: 99%

A Poly-ADP-Ribose Trigger Releases the Auto-Inhibition of a Chromatin Remodeling Oncogene

et al. 2017

View full text Add to dashboard Cite

DNA damage triggers chromatin remodeling by mechanisms that are poorly understood. The oncogene and chromatin remodeler ALC1/CHD1L massively decompacts chromatin in vivo yet is inactive prior to DNA-damage-mediated PARP1 induction. We show that the interaction of the ALC1 macrodomain with the ATPase module mediates auto-inhibition. PARP1 activation suppresses this inhibitory interaction. Crucially, release from auto-inhibition requires a poly-ADP-ribose (PAR) binding macrodomain. We identify tri-ADP-ribose as a potent PAR-mimic and synthetic allosteric effector that abrogates ATPase-macrodomain interactions, promotes an ungated conformation, and activates the remodeler's ATPase. ALC1 fragments lacking the regulatory macrodomain relax chromatin in vivo without requiring PARP1 activation. Further, the ATPase restricts the macrodomain's interaction with PARP1 under non-DNA damage conditions. Somatic cancer mutants disrupt ALC1's auto-inhibition and activate chromatin remodeling. Our data show that the NAD-metabolite and nucleic acid PAR triggers ALC1 to drive chromatin relaxation. Modular allostery in this oncogene tightly controls its robust, DNA-damage-dependent activation.

show abstract

Section: Discussionmentioning

confidence: 99%

A Poly-ADP-Ribose Trigger Releases the Auto-Inhibition of a Chromatin Remodeling Oncogene

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The HCC cell lines (Huh7, Bel-7402, and HepG2) were cultured in DMEM medium (Gibco, USA), supplemented with 10 % fetal bovine serum, 50 U/mol penicillin and 50 mg/ml streptomycin (Sigma-Aldrich, USA) and maintained in a humidified incubator at 37 °C with 5 % CO2. All cell lines were obtained from Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China, and their background information has been described 20 - 22 . Cellular hypoxia was performed by use of Cobalt Chloride (CoCl2, Sigma-Aldrich, USA).…”

Section: Methodsmentioning

confidence: 99%

The Expression of FAP in Hepatocellular Carcinoma Cells is Induced by Hypoxia and Correlates with Poor Clinical Outcomes

Zou¹,

Liu²,

Zhang³

et al. 2018

J. Cancer

View full text Add to dashboard Cite

Fibroblast activation protein (FAP) is a serine protease that has been reported in fibroblasts and some carcinoma cells, which correlates with poor patient outcomes. FAP can be induced under hypoxia which is also vital in the malignant behaviors of cancer cells. However, the role of FAP and its correlation with hypoxia has not been investigated in HCC cancer cells. In tissues from post-surgical HCC patients in our center, we adopted immunohistochemistry staining (IHC), western blot and quantitative RT-PCR to detect the expression levels of FAP and the hypoxia related marker, hypoxia inducible factor 1α (HIF-1α). X-tile software was used for the determination of high and low expression of FAP and HIF-1α after the IHC analysis. Clinicopathological analysis, Kaplan-Meier analysis and Cox regression model were performed. In-vitro experiments were performed to confirm the relationship between FAP and hypoxia in HCC cancer cell lines (HepG2, Huh7 and MHCC97H). Results revealed that expression levels of FAP and HIF-1α were significantly correlated (Pearson r2 = 0.2753, p < 0.0001) in IHC analysis of the 138-patient cohort. Western blot and quantity RT-PCR indicated parallel changes in 11 post-surgical fresh frozen tissues. The HIF-1α and FAP expression were associated with serum AFP, TNM, tumor size and vascular invasion. Cox regression analysis showed that HIF-1α/ FAP combination were the independent predictor for overall survival (OS) and time-to-recurrence (TTR) in post-surgical HCC patients. Kaplan-Meier analyses revealed that the patient with high levels of HIF-1α, FAP and combined HIF-1α/FAP had the shortest OS and TTR. In-vitro experiments showed that FAP was increased in hypoxic HCC cancer cell lines in parallel with that of HIF-1α and three EMT markers (E-cadherin, Snail and TWIST). In conclusion, the up-regulation of FAP in HCC cancer cells under hypoxia can be indicative of poor prognosis in patients.

show abstract

“…The HCC cancer cell line Huh7 was obtained from Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China. 16 The HSC line LX2 (Merck Millipore, Billerica, MA, USA) 17 was obtained from Fudan University, Shanghai, China. The use of the cell lines was approved by the Institutional Ethical Review Board of The Fifth Affiliated Hospital, Sun Yat-sen University.…”

Section: Methodsmentioning

confidence: 99%

A novel 12-marker panel of cancer-associated fibroblasts involved in progression of hepatocellular carcinoma

Zou¹,

Liu²,

Gong³

et al. 2018

CMAR

View full text Add to dashboard Cite

Background/AimCancer-associated fibroblasts (CAFs) are important factors in the progression of hepatocellular carcinoma (HCC). But the characterization of these cells remains incomplete. This study aims to identify a panel of markers for CAFs that are associated with HCC progression.Materials and methodsThe sequencing data and clinicopathological characteristics of 366 patients were obtained from the Cancer Genome Atlas (TCGA) database (366 HCC tissues and there were 50/366 cases with corresponding normal liver tissues). In vitro validation of the markers was performed by quantitative real-time PCR using the hepatic stellate cell line LX2 induced by the HCC cell line Huh7. The activation of LX2 was confirmed by α-smooth muscle actin and fibroblast activation protein, using quantitative real-time PCR and immunofluorescence staining. In vivo detections of the 12 markers were done in 40 tissue samples (30 HCC and 10 normal).ResultsWe successfully identified 12 CAF markers from TCGA data: FGF5, CXCL5, IGFL2, MMP1, ADAM32, ADAM18, IGFL1, FGF8, FGF17, FGF19, FGF4, and FGF23. The 12-marker panel was associated with the pathological and clinical progressions of HCC. All 12 markers were upregulated in vitro. In vivo expressions of these markers were paralleled with those in TCGA data.ConclusionA 12-marker panel of CAFs in HCC is identified, which is associated with both pathological and clinical progressions of cancer.

show abstract

CHD1L promotes lineage reversion of hepatocellular carcinoma through opening chromatin for key developmental transcription factors

Cited by 30 publications

References 38 publications

A Poly-ADP-Ribose Trigger Releases the Auto-Inhibition of a Chromatin Remodeling Oncogene

A Poly-ADP-Ribose Trigger Releases the Auto-Inhibition of a Chromatin Remodeling Oncogene

The Expression of FAP in Hepatocellular Carcinoma Cells is Induced by Hypoxia and Correlates with Poor Clinical Outcomes

A novel 12-marker panel of cancer-associated fibroblasts involved in progression of hepatocellular carcinoma

Contact Info

Product

Resources

About