CUDR promotes liver cancer stem cell growth through upregulating TERT and C-Myc

Hu, Pu; Zheng, Qidi; Li, Haiyan; Wu, Mengying; An, Jiahui; Gui, Xin; Li, Tianming; Lu, Dongdong

doi:10.18632/oncotarget.5805

Cited by 76 publications

(64 citation statements)

References 48 publications

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“…TERRA associates with SUV39H1 H3K9 histone methyltransferase, which promotes accumulation of H3K9me3 at damaged telomeres and end-to-end fusions47. CUDR promotes liver cancer stem cell growth through upregulating TERT and C-Myc48. This assertion is based on several observations in HULC and/ot MALAT1 overexpresed liver cancer stem cells: (1) Upregulated lncRNA MALAT1/HULC were positively associated with the TRF2 expression in human liver cancer tissues.…”

Section: Discussionmentioning

confidence: 99%

HULC cooperates with MALAT1 to aggravate liver cancer stem cells growth through telomere repeat-binding factor 2

Lin

et al. 2016

Sci Rep

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The dysregulation of lncRNAs has increasingly been linked to many human diseases, especially in cancers. Our results demonstrate HULC, MALAT1 and TRF2 are highly expressed in human hepatocellular carcinoma tissues, and HULC plus MALAT1 overexpression drastically promotes the growth of liver cancer stem cells. Mechanistically, both HULC and MALAT1 overexpression enhanced RNA polII, P300, CREPT to load on the promoter region of telomere repeat-binding factor 2(TRF2), triggering the overexpression, phosphorylation and SUMOylation of TRF2. Strikingly, the excessive TRF2 interacts with HULC or MALAT1 to form the complex that loads on the telomeric region, replacing the CST/AAF and recruiting POT1, pPOT1, ExoI, SNM1B, HP1 α. Accordingly, the telomere is greatly protected and enlonged. Furthermore, the excessive HULC plus MALAT1 reduced the methylation of the TERC promoter dependent on TRF2, increasing the TERC expression that causes the increase of interplay between TRET and TERC. Ultimately, the interaction between RFC and PCNA or between CDK2 and CyclinE, the telomerase activity and the microsatellite instability (MSI) are significantly increased in the liver cancer stem cells. Our demonstrations suggest that haploinsufficiency of HULC/MALAT1 plays an important role in malignant growth of liver cancer stem cell.

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Section: Discussionmentioning

confidence: 99%

HULC cooperates with MALAT1 to aggravate liver cancer stem cells growth through telomere repeat-binding factor 2

Lin

et al. 2016

Sci Rep

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“…Cell isolation and culture. Human normal liver stem cells and HCC stem cells were isolated from liver tissues of HCC patients at our hospital according to a previous study (26). Briefly, cell suspensions were centrifuged at 300 x g for 10 min and cell pellets were resuspended in 300 µl of buffer/10 8 total cells after aspirating the supernatant completely.…”

Section: Docetaxel Promotes Cell Apoptosis and Decreases Sox2 Expressionmentioning

confidence: 99%

Docetaxel promotes cell apoptosis and decreases SOX2 expression in CD133‑expressing hepatocellular carcinoma stem cells by suppressing the PI3K/AKT signaling pathway

Shao

Cui

et al. 2018

Oncol Rep

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Docetaxel is a front-line standard-of-care chemotherapeutic drug for the treatment of cancers. However, the underlying function and mechanism of docetaxel in human hepatocellular carcinoma (HCC) are uncertain. Therefore, the present study aimed to determine the effects of docetaxel on cell apoptosis and SOX2 expression in cultured human HCC stem cells. After human HCC stem cells were treated with docetaxel, cell proliferation was assessed by methyl thiazolyl tetrazolium (MTT) method, the cell apoptotic rate was evaluated by flow cytometry, the expression of CD133 and sex determining region Y-box 2 (SOX2) was determined by RT-PCR and immunohistochemistry, and the protein levels of CD133, SOX2, phosphoinositide 3-kinases (PI3K), AKT and phosphorylated AKT (p-AKT) were analyzed by western blotting. The results indicated that SOX2 and CD133 were highly expressed in patients with HCC while their expression was significantly decreased after patients with HCC were treated with docetaxel. In vitro, docetaxel inhibited the proliferation while it enhanced the apoptosis of human CD133-expressing HCC stem cells. Furthermore, lower expression of p-AKT and SOX2 were revealed in the presence of docetaxel. Notably, docetaxel-inhibited SOX2 expression and growth of human CD133-expressing HCC stem cells were partially restricted following the block of the PI3K/AKT signaling pathway using the inhibitor LY294002. The present study collectively indicated that docetaxel promoted apoptosis and upregulated SOX2 expression of human HCC stem cells through the suppression of the PI3K/AKT signaling pathway.

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“…Abnormal c-myc expression, often as a result of direct gene alteration, is associated with tumorigenesis and sustained tumor growth [2–4]. Many factors may cause c-myc gene expression disorders, such as oncogene activation or tumor suppressor loss or inactivation [5]. According to recent studies, about 20% of human tumors can be associated with c-myc overexpression.…”

Section: Introductionmentioning

confidence: 99%

Quinazoline derivative QPB-15e stabilizes the c-myc promoter G-quadruplex and inhibits tumor growth in vivo

et al. 2016

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The ribozyme-sensitive element NHE-III1 in the P1 promoter region of the important proto-oncogene c-myc contains many guanine (G)-rich sequences. Induction and stabilization of the G-quadruplex formed by NHE-III1 can downregulate c-myc expression. In the present study, we found that QPB-15e, a quinazoline derivative designed and synthesized by our laboratory, binds to and stabilizes the c-myc G-quadruplex in vitro, thereby inhibiting double-stranded DNA replication, downregulating c-myc gene expression and arresting cancer cell proliferation. PCR termination experiments showed that QPB-15e blocked double-stranded DNA replication by inducing or stabilizing the c-myc G-quadruplex. FRET-melting further confirmed that QPB-15e improved the stability of the G-quadruplex, and CD spectroscopy indicated that the compound interacted directly with the G-rich sequence. In competitive dialysis experiments, QPB-15e bound preferentially to quadruplex DNA in various structures, especially the G-quadruplex within the c-myc promoter region. Moreover, QPB-15e reduced the weights and volumes of tumors transplanted into nude mice. These findings strongly suggest that QPB-15e is a c-myc G-quadruplex ligand with anti-tumor properties, and may be efficacious for treating cancer in humans.

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CUDR promotes liver cancer stem cell growth through upregulating TERT and C-Myc

Cited by 76 publications

References 48 publications

HULC cooperates with MALAT1 to aggravate liver cancer stem cells growth through telomere repeat-binding factor 2

HULC cooperates with MALAT1 to aggravate liver cancer stem cells growth through telomere repeat-binding factor 2

Docetaxel promotes cell apoptosis and decreases SOX2 expression in CD133‑expressing hepatocellular carcinoma stem cells by suppressing the PI3K/AKT signaling pathway

Quinazoline derivative QPB-15e stabilizes the c-myc promoter G-quadruplex and inhibits tumor growth in vivo

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