The long non-coding RNA Linc-GALH promotes hepatocellular carcinoma metastasis via epigenetically regulating Gankyrin

Xu, Xiaoliang; Lou, Yun; Tang, Junwei; Teng, Yue; Zhang, Zechuan; Yin, Yin; Han, Ze‐Guang; Tan, Zhongming

doi:10.1038/s41419-019-1348-0

Cited by 36 publications

(25 citation statements)

References 35 publications

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“…We found that the transcription factor STAT3, which is recruited by gankyrin, directly binds to the promoter of CCL24 and triggers its transcription in ccRCC. In addition, although some previous studies have shown that the long noncoding RNA Linc-GALH promotes gankyrin/AKT signaling by controlling the methylation status of gankyrin or KIFC1, the upstream regulators should be further studied to determine an effective inhibitor for gankyrin signaling in tumors 32 . Our study found that autocrine CCL24 can trigger the expression and transcription of gankyrin in ccRCC via CCR3, which has not been previously reported.…”

Section: Discussionmentioning

confidence: 99%

Blocking the autocrine regulatory loop of Gankyrin/STAT3/CCL24/CCR3 impairs the progression and pazopanib resistance of clear cell renal cell carcinoma

Wang

Hong

et al. 2020

Cell Death Dis

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The poor prognosis of clear-cell renal cell carcinoma (ccRCC) patients is due to progression and targeted drug resistance, but the underlying molecular mechanisms need further elucidation. This study examined the biological function and related mechanisms of gankyrin in ccRCC based on the results of our previous study. To this end, in vitro functional experiments; in vivo models of subcutaneous tumor formation, lung metastasis, and orthotopic ccRCC; and antibody chip detection, co-IP, ChIP assays were performed to examine the biological role and molecular mechanisms of gankyrin in ccRCC. Two hundred fifty-six ccRCC patients were randomly divided into training and validation cohorts to examine the prognostic value of gankyrin and other markers through IHC and statistical analyses. We observed that the gankyrin-overexpressing ccRCC cell lines 786-O and 769-P exhibited increased proliferation, invasion, migration, tumorigenicity, and pazopanib resistance and decreased apoptosis, while gankyrin knockdown achieved the opposite results. Mechanistically, gankyrin recruited STAT3 via direct binding, and STAT3 binding to the CCL24 promoter promoted its expression. Reciprocally, an increase in autocrine CCL24 enhanced the expression of gankyrin and STAT3 activation via CCR3 in ccRCC, forming a positive autocrine-regulatory loop. Furthermore, in vivo experimental results revealed that blocking the positive loop through gankyrin knockdown or treatment with the CCR3 inhibitor SB328437 reversed the resistance to pazopanib and inhibited lung metastasis in ccRCC. Moreover, a positive correlation between gankyrin and STAT3 or CCL24 expression in ccRCC specimens was observed, and improved accuracy for ccRCC patient prognosis was achieved by combining gankyrin and STAT3 or CCL24 expression with existing clinical prognostic indicators, including the TNM stage and SSIGN score. In summary, targeting the gankyrin/STAT3/CCL24/CCR3 autocrine-regulatory loop may serve as a remedy for patients with advanced ccRCC, and combining gankyrin and STAT3 or CCL24 expression with the current clinical indicators better predicts ccRCC patient prognosis.

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Section: Discussionmentioning

confidence: 99%

Blocking the autocrine regulatory loop of Gankyrin/STAT3/CCL24/CCR3 impairs the progression and pazopanib resistance of clear cell renal cell carcinoma

Wang

Hong

et al. 2020

Cell Death Dis

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“…lncRNA GAS5 functions as a tumor suppressor in HCC metastasis through directly interacting with miR-182 and low level of GAS5 correlates with poor outcomes [26]. lncRNA GALH promotes HCC metastasis via epigenetically regulating Gankyrin and acts as an independent unfavorable prognostic indicator [27]. In this study, we focused on the newly identified lncRNA NKILA, evaluated the clinicopathological significance of NKILA in HCC patients and investigated the function and mechanism of NKILA on HCC cell biological behavior.…”

Section: Discussionmentioning

confidence: 99%

NKILA, a prognostic indicator, inhibits tumor metastasis by suppressing NF-κB/Slug mediated epithelial-mesenchymal transition in hepatocellular carcinoma

et al. 2020

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The metastasis of hepatocellular carcinoma (HCC) is one of the major obstacles hindering its therapeutic efficacy, leading to low surgical resection rate, high mortality and poor prognosis. Accumulating evidence has shown that both long noncoding RNA (lncRNA) and NF-κB play vital roles in the regulation of cancer metastasis. However, the clinical significance and biological function of NKILA (NF-κB interacting lncRNA) and its interaction with NF-κB in HCC remain unknown. In this study, we demonstrated that NKILA was down-regulated in HCC tissues and cell lines, and decreased NKILA expression was significantly associated with larger tumor size and positive vascular invasion in HCC patients. NKILA reduction was an independent risk factor of HCC patients' poor prognosis, and the 5-year overall survival (OS) rates of patients with low and high NKILA expression were 15.6% and 60.0%, respectively. Moreover, NKILA inhibits migration and invasion of HCC cells both in vitro and in vivo. Mechanistically, NKILA prevents Slug/epithelial to mesenchymal transition (EMT) pathway via suppressing phosphorylation of IκBα, p65 nuclear translocation and NF-κB activation. In conclusion, these results indicate that NKILA might serve as an effective prognostic biomarker and a promising therapeutic target against HCC metastasis.

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“…Histone methylation and DNA methylation, as important epigenetic modification manners, are involved in modulating the expression of numerous cancer-related genes [48,49]. For instance, a recent study revealed that linc-GALH (Gankyrin associated lincRNA in hepatocellular carcinoma), which might be a new biomarker for judging HCC metastasis, could promote the degradation of DNMT1 (DNA methyltransferase 1) by enhancing the ubiquitination and expression of Gankyrin (standard nomenclature is PSMD10) by lowering the methylation state in HCC [18]. Considerable evidence suggests that the EMT (epithelial-mesenchymal transition) is responsible for the metastasis and recurrence of tumors, including HCC.…”

Section: Lncrnas As Novel Regulators In Hcc Metastasismentioning

confidence: 99%

“…LncRNA PTTG3P (pituitary tumor-transforming 3, pseudogene) promotes the growth and metastasis of HCC by up-regulating PTTG1 and activating PI3K/AKT signaling [65]. The lncRNA-AWPPH linc-GALH, which can promote the metastasis of HCC, is also involved in the regulation of AKT signaling pathway [18,35]. Furthermore, Linc00974 promotes the proliferation and metastasis via interacting with KRT19 (Keratin 19) in HCC.…”

Section: Pathways Controlled By Lncrnas In Hcc Metastasismentioning

confidence: 99%

The Emerging Role of Long Non-Coding RNAs in the Metastasis of Hepatocellular Carcinoma

et al. 2019

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Long non-coding RNAs (lncRNAs) play multifaceted roles in modulating gene expression under both physiological and pathological processes. The dysregulation of lncRNAs has been increasingly linked with many human diseases, including a plethora of cancers. Mounting evidence indicates that lncRNAs are aberrantly expressed in hepatocellular carcinoma (HCC) and can regulate HCC progression, as well as metastasis. In this review, we summarize the recent findings on the expanding roles of lncRNAs in modulating various functions of HCC, and elaborate on how can lncRNAs impact HCC metastasis and progression via interacting with chromatin, RNA, and proteins at the epigenetic, transcriptional, and post-transcriptional levels. This mini-review also highlights the current advances regarding the signaling pathways of lncRNAs in HCC metastasis and sheds light on the possible application of lncRNAs for the prevention and treatment of HCC.

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The long non-coding RNA Linc-GALH promotes hepatocellular carcinoma metastasis via epigenetically regulating Gankyrin

Cited by 36 publications

References 35 publications

Blocking the autocrine regulatory loop of Gankyrin/STAT3/CCL24/CCR3 impairs the progression and pazopanib resistance of clear cell renal cell carcinoma

Blocking the autocrine regulatory loop of Gankyrin/STAT3/CCL24/CCR3 impairs the progression and pazopanib resistance of clear cell renal cell carcinoma

NKILA, a prognostic indicator, inhibits tumor metastasis by suppressing NF-κB/Slug mediated epithelial-mesenchymal transition in hepatocellular carcinoma

The Emerging Role of Long Non-Coding RNAs in the Metastasis of Hepatocellular Carcinoma

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