The HLJ1 -targeting drug screening identified Chinese herb andrographolide that can suppress tumour growth and invasion in non-small-cell lung cancer

Lai, Yi-Hua; Yu, Sung‐Liang; Chen, Hsuan‐Yu; Wang, Chi-Chung; Chen, Huei‐Wen; Chen, Jeremy J.W.

doi:10.1093/carcin/bgt005

Cited by 42 publications

(32 citation statements)

References 41 publications

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“…Two herbal chemicals, curcumin (Chen et al, 2008) and andrographolide (Lai et al, 2013), were shown to induce HLJ1 expression and suppress tumorigenesis in lung adenocarcinoma and nonsmall cell lung cancer, respectively. High concentration of DMSO ( ‡1%) was also shown to induce HLJ1 and inhibit malignant properties of lung adenocarcinoma cells (Wang et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…In this context, HLJ1 (DNAJB4) belongs to the DNAJ (HSP40) family of HSPs and is regarded as a tumor suppressor gene in lung, colon, and gastric cancers (Liu et al, 2014;Simões-correia et al, 2014;Tsai et al, 2006;Wang et al, 2005). HLJ1 has also been suggested as a potential biomarker and therapeutic target in lung cancer (Chen et al, 2008;Lai et al, 2013;Tsai et al, 2006;Wang et al, 2007). Moreover, in vitro studies showed that induction of HLJ1 inhibits cancer cell invasion in hepatocellular carcinoma cells (Wang et al, 2007).…”

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confidence: 99%

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HLJ1 (DNAJB4) Gene Is a Novel Biomarker Candidate in Breast Cancer

Acun

Doberstein

Habermann

et al. 2017

OMICS: A Journal of Integrative Biology

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Breast cancer is the most common cancer type and cause of cancer-related mortality among women worldwide. New biomarker discovery is crucial for diagnostic innovation and personalized medicine in breast cancer. Heat shock proteins (HSPs) have been increasingly reported as biomarkers and potential drug targets for cancers. HLJ1 (DNAJB4) belongs to the DNAJ (HSP40) family of HSPs and is regarded as a tumor suppressor gene in lung, colon, and gastric cancers. However, the role of the HLJ1 gene in breast cancer is currently unknown. We evaluated the role of the HLJ1 gene in breast cancer progression by analyzing its in vitro and in vivo expression and its genetic/epigenetic alterations. HLJ1 expression was found to be reduced or lost in breast cancer cell lines (SK-BR-3, MDA-MB-231, ZR-75-1) compared with the nontumorigenic mammary epithelial cell line (MCF 10A). In a clinical context for breast cancer progression, the HLJ1 expression was significantly less frequent in invasive breast carcinoma samples (n = 230) compared with normal breast tissue (n = 100), benign neoplasia (n = 53), and ductal carcinoma in situ (n = 21). In methylation analyses by the combined bisulfite restriction analysis assay, the CpG island located in the 5¢-flanking region of the HLJ1 gene was found to be methylated in breast cancer cell lines. HLJ1 expression was restored in the ZR-75-1 cell line by DNA demethylating agent 5-Aza-2¢-deoxycytidine (5-AzadC) and histone deacetylase inhibitor trichostatin A. These new observations support the idea that HLJ1 is a tumor suppressor candidate and potential biomarker for breast cancer. Epigenomic mechanisms such as CpG methylation and histone deacetylation might contribute to downregulation of HLJ1 expression. We call for future functional, epigenomic, and clinical studies to ascertain the contribution of HLJ1 to breast cancer pathogenesis and, importantly, evaluate its potential for biomarker development in support of personalized medicine diagnostic innovation in clinical oncology.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

HLJ1 (DNAJB4) Gene Is a Novel Biomarker Candidate in Breast Cancer

Acun

Doberstein

Habermann

et al. 2017

OMICS: A Journal of Integrative Biology

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“…Therefore, while these inhibitors do not bind directly to Hsp40, they provide a proof of concept for the disruption of the Hsp70 chaperone through inhibition of Hsp40 binding. The natural product andrographolide, isolated from a Chinese herb, is another natural compound that influences the function of Hsp40 [138]. This compound was identified in a screen of natural compounds with the ability to activate the promoter of the Hsp40 protein DNAJB4.…”

Section: Naturally Occurring Inhibitorsmentioning

confidence: 99%

Hsp40 Co-chaperones as Drug Targets: Towards the Development of Specific Inhibitors

Pesce

Blatch

Edkins

2015

Topics in Medicinal Chemistry

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The heat shock protein 40 (Hsp40/DNAJ) family of co-chaperones modulates the activity of the major molecular chaperone heat shock protein 70 (Hsp70) protein group. Hsp40 stimulates the basal ATPase activity of Hsp70 and hence regulates the affinity of Hsp70 for substrate proteins. The number of Hsp40 genes in most organisms is substantially greater than the number of Hsp70 genes. Therefore, different Hsp40 family members may regulate different activities of the same Hsp70. This fact, along with increasing knowledge of the function of Hsp40 in diseases, has led to certain Hsp40 isoforms being considered promising drug targets. Here we review the role of Hsp40 in human disease and recent developments towards the creation of Hsp40-specific inhibitors.

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“…Using the HLJ1 promoter and luciferase reporter assays, the HLJ1-targeting drug-screening platform was established to screen and identify traditional Chinese herbs that can target the novel tumour suppressor gene HLJ1. Among the herbal drugs identified, the andrographolide is a promising new anticancer agent that could significantly induced HLJ1 expression and suppress tumour growth and invasion in NSCLC [90] . Andrographolide, a diterpenoid lactone isolated from the Chinese herbal medicine Andrographis paniculata, is known for its wide pharmacological activities, such as its anti-inflammatory, antiangiogenesis, pro-apoptosis and anticancer activities [91] .…”

Section: Hlj1 As a Molecular Target In Anticancer Therapiesmentioning

confidence: 99%

“…Using this platform, we identified andrographolide as a promising new anticancer agent that could suppress tumour growth and invasion in NSCLC. The onco-suppressive effects of andrographolide may be partially mediated by JunB-regulated HLJ1 expression, which modulates the transcription factor AP-2α binding at the MMP2 promoter and represses the expression of MMP2 [90] . In addition, silencing HLJ1 partially reverses the inhibition of cancer cell invasion by andrographolide.…”

Section: Hlj1 As a Molecular Target In Anticancer Therapiesmentioning

confidence: 99%

Tumour suppressor HLJ1: A potential diagnostic, preventive and therapeutic target in non-small cell lung cancer

Tsai¹

2014

WJCO

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Lung cancer is the leading cause of cancer-related mortality throughout the world. Non-small cell lung cancer (NSCLC) accounts for 85% of all diagnosed lung cancers. Despite considerable progress in the diagnosis and treatment of the disease, the overall 5-year survival rate of NSCLC patients remains lower than 15%. The most common causes of death in lung cancer patients are treatment failure and metastasis. Therefore, developing novel strategies that target both tumour growth and metastasis is an important and urgent mission for the next generation of anticancer therapy research. Heat shock proteins (HSPs), which are involved in the fundamental defence mechanism for maintaining cellular viability, are markedly activated during environmental or pathogenic stress. HSPs facilitate rapid cell division, metastasis, and the evasion of apoptosis in cancer development. These proteins are essential players in the development of cancer and are prime therapeutic targets. In this review, we focus on the current understanding of the molecular mechanisms responsible for HLJ1's role in lung cancer carcinogenesis and progression. HLJ1, a member of the human HSP 40 family, has been characterised as a tumour suppressor. Research studies have also reported that HLJ1 shows promising dual anticancer effects, inhibiting both tumour growth and metastasis in NSCLC. The accumulated evidence suggests that HLJ1 is a potential biomarker and treatment target for NSCLC.© 2014 Baishideng Publishing Group Inc. All rights reserved.Key words: Non-small cell lung cancer; Metastasis; HLJ1; Anticancer; Biomarker Core tip: HLJ1, a member of the human heat shock proteins 40 family, has been characterised as a tumour suppressor. Research studies have reported that HLJ1 shows promising dual anticancer effects, inhibiting both tumour growth and metastasis in non-small cell lung cancer (NSCLC). The accumulated evidence suggests that HLJ1 is a potential biomarker and treatment target for NSCLC. We propose a hypothetical model for the roles of HLJ1 stimulator in suppressing lung cancer tumourigenesis. Investigating the integrated and coordinated molecular mechanisms of HLJ1 may shed new light on the treatment of lung cancer. The development of drug targeting HLJ1 may be an effective approach for lung cancer therapy.Tsai MF, Wang CC, Chen JJW. Tumour suppressor HLJ1: A potential diagnostic, preventive and therapeutic target in nonsmall cell lung cancer.

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The HLJ1 -targeting drug screening identified Chinese herb andrographolide that can suppress tumour growth and invasion in non-small-cell lung cancer

Cited by 42 publications

References 41 publications

HLJ1 (DNAJB4) Gene Is a Novel Biomarker Candidate in Breast Cancer

HLJ1 (DNAJB4) Gene Is a Novel Biomarker Candidate in Breast Cancer

Hsp40 Co-chaperones as Drug Targets: Towards the Development of Specific Inhibitors

Tumour suppressor HLJ1: A potential diagnostic, preventive and therapeutic target in non-small cell lung cancer

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