Limits...
HOTAIR is a therapeutic target in glioblastoma.

Zhou X, Ren Y, Zhang J, Zhang C, Zhang K, Han L, Kong L, Wei J, Chen L, Yang J, Wang Q, Zhang J, Yang Y, Jiang T, Li M, Kang C - Oncotarget (2015)

Bottom Line: An intracranial animal model was used to confirm that HOTAIR depletion inhibited GBM cell migration/invasion.In the orthotopic model, HOTAIR was required for GBM formation in vivo.In summary, HOTAIR is a potential therapeutic target in GBM.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin 300052, China.

ABSTRACT
HOTAIR is a negative prognostic factor and is overexpressed in multiple human cancers including glioblastoma multiform (GBM). Survival analysis of Chinese Glioma Genome Atlas (CGGA) patient data indicated that high HOTAIR expression was associated with poor outcome in GBM patients. NLK (Nemo-like kinase), a negative regulator of the β-catenin pathway, was negatively correlated with HOTAIR expression. When the β-catenin pathway was inhibited, GBM cells became susceptible to cell cycle arrest and inhibition of invasion. Introduction of the HOTAIR 5' domain in human glioma-derived astrocytoma induced β-catenin. An intracranial animal model was used to confirm that HOTAIR depletion inhibited GBM cell migration/invasion. In the orthotopic model, HOTAIR was required for GBM formation in vivo. In summary, HOTAIR is a potential therapeutic target in GBM.

No MeSH data available.


Related in: MedlinePlus

HOTAIR regulates GBM cell cycle progression in vitro(A) The cell cycle distribution of U87 and U87vIII cells treated with Lenti-HOTAIR si and Lenti-NC was determined by FCM. (B) The cell cycle distribution of U87 and U87vIII cells treated with DZNEP and 2PCPA was determined by FCM. (C) Lenti-HOTAIR si treatment increased the expression of RB, p21 and p16 and the levels of p-RB, whereas the expression of cyclin D1 and E2F1 was inhibited in U87 and U87vIII cells. (D) DZNEP treatment induced the expression of p21 and increased the levels of p-RB while inhibiting cyclin D1 expression in U87 and U87vIII cells. (E) Treatment with Lenti-HOTAIR 5′ domain inhibited the expression of RB and decreased levels of p-RB while inducing the expression of cyclin D1 in an astrocytoma primary culture. GAPDH was used as a loading control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4480757&req=5

Figure 4: HOTAIR regulates GBM cell cycle progression in vitro(A) The cell cycle distribution of U87 and U87vIII cells treated with Lenti-HOTAIR si and Lenti-NC was determined by FCM. (B) The cell cycle distribution of U87 and U87vIII cells treated with DZNEP and 2PCPA was determined by FCM. (C) Lenti-HOTAIR si treatment increased the expression of RB, p21 and p16 and the levels of p-RB, whereas the expression of cyclin D1 and E2F1 was inhibited in U87 and U87vIII cells. (D) DZNEP treatment induced the expression of p21 and increased the levels of p-RB while inhibiting cyclin D1 expression in U87 and U87vIII cells. (E) Treatment with Lenti-HOTAIR 5′ domain inhibited the expression of RB and decreased levels of p-RB while inducing the expression of cyclin D1 in an astrocytoma primary culture. GAPDH was used as a loading control.

Mentions: Our previous report indicated that HOTAIR knockdown blocked the cell cycle at G1 phase [16]. To further study the underlying mechanism of this phenomenon, we compared the cell cycle distribution after treatment with Lenti-HOTAIR si and the EZH2 inhibitor for 48 hr. Flow cytometry data revealed that both HOTAIR-depleted U87 and U87vIII GBM cells increased about 1.3–1.5 fold in G1 phase and a decreased 1.4–1.7 fold in replicating S phase (Figure 4A, P < 0.05). The tumor suppressor retinoblastoma protein (RB) and the CDK inhibitors p21 and p16 were upregulated upon HOTAIR knockdown. Notably, HOTAIR-depleted cells also showed an increased level of phosphorylated RB (Figure 4C). Cell cycle arrest phenotypes, including G1 arrest, and a significant reduction in the percentage of cells in S phase were also observed in DZNEP-treated U87 and U87vIII cells, whereas 2PCPA treatment did not affect the cell cycle (Figure 4B and 4D). Moreover, we overexpressed the HOTAIR 3′ or 5′ domain in an astrocytoma-derived primary culture (Figure 4E). Western blots indicated that overexpression of the 5′ domain decreased the levels of pRB and upregulated cyclinD1 expression. These data provide important evidence that the HOTAIR 5′ domain binds to EZH2 in GBM cells and regulates cell cycle progression.


HOTAIR is a therapeutic target in glioblastoma.

Zhou X, Ren Y, Zhang J, Zhang C, Zhang K, Han L, Kong L, Wei J, Chen L, Yang J, Wang Q, Zhang J, Yang Y, Jiang T, Li M, Kang C - Oncotarget (2015)

HOTAIR regulates GBM cell cycle progression in vitro(A) The cell cycle distribution of U87 and U87vIII cells treated with Lenti-HOTAIR si and Lenti-NC was determined by FCM. (B) The cell cycle distribution of U87 and U87vIII cells treated with DZNEP and 2PCPA was determined by FCM. (C) Lenti-HOTAIR si treatment increased the expression of RB, p21 and p16 and the levels of p-RB, whereas the expression of cyclin D1 and E2F1 was inhibited in U87 and U87vIII cells. (D) DZNEP treatment induced the expression of p21 and increased the levels of p-RB while inhibiting cyclin D1 expression in U87 and U87vIII cells. (E) Treatment with Lenti-HOTAIR 5′ domain inhibited the expression of RB and decreased levels of p-RB while inducing the expression of cyclin D1 in an astrocytoma primary culture. GAPDH was used as a loading control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480757&req=5

Figure 4: HOTAIR regulates GBM cell cycle progression in vitro(A) The cell cycle distribution of U87 and U87vIII cells treated with Lenti-HOTAIR si and Lenti-NC was determined by FCM. (B) The cell cycle distribution of U87 and U87vIII cells treated with DZNEP and 2PCPA was determined by FCM. (C) Lenti-HOTAIR si treatment increased the expression of RB, p21 and p16 and the levels of p-RB, whereas the expression of cyclin D1 and E2F1 was inhibited in U87 and U87vIII cells. (D) DZNEP treatment induced the expression of p21 and increased the levels of p-RB while inhibiting cyclin D1 expression in U87 and U87vIII cells. (E) Treatment with Lenti-HOTAIR 5′ domain inhibited the expression of RB and decreased levels of p-RB while inducing the expression of cyclin D1 in an astrocytoma primary culture. GAPDH was used as a loading control.
Mentions: Our previous report indicated that HOTAIR knockdown blocked the cell cycle at G1 phase [16]. To further study the underlying mechanism of this phenomenon, we compared the cell cycle distribution after treatment with Lenti-HOTAIR si and the EZH2 inhibitor for 48 hr. Flow cytometry data revealed that both HOTAIR-depleted U87 and U87vIII GBM cells increased about 1.3–1.5 fold in G1 phase and a decreased 1.4–1.7 fold in replicating S phase (Figure 4A, P < 0.05). The tumor suppressor retinoblastoma protein (RB) and the CDK inhibitors p21 and p16 were upregulated upon HOTAIR knockdown. Notably, HOTAIR-depleted cells also showed an increased level of phosphorylated RB (Figure 4C). Cell cycle arrest phenotypes, including G1 arrest, and a significant reduction in the percentage of cells in S phase were also observed in DZNEP-treated U87 and U87vIII cells, whereas 2PCPA treatment did not affect the cell cycle (Figure 4B and 4D). Moreover, we overexpressed the HOTAIR 3′ or 5′ domain in an astrocytoma-derived primary culture (Figure 4E). Western blots indicated that overexpression of the 5′ domain decreased the levels of pRB and upregulated cyclinD1 expression. These data provide important evidence that the HOTAIR 5′ domain binds to EZH2 in GBM cells and regulates cell cycle progression.

Bottom Line: An intracranial animal model was used to confirm that HOTAIR depletion inhibited GBM cell migration/invasion.In the orthotopic model, HOTAIR was required for GBM formation in vivo.In summary, HOTAIR is a potential therapeutic target in GBM.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin 300052, China.

ABSTRACT
HOTAIR is a negative prognostic factor and is overexpressed in multiple human cancers including glioblastoma multiform (GBM). Survival analysis of Chinese Glioma Genome Atlas (CGGA) patient data indicated that high HOTAIR expression was associated with poor outcome in GBM patients. NLK (Nemo-like kinase), a negative regulator of the β-catenin pathway, was negatively correlated with HOTAIR expression. When the β-catenin pathway was inhibited, GBM cells became susceptible to cell cycle arrest and inhibition of invasion. Introduction of the HOTAIR 5' domain in human glioma-derived astrocytoma induced β-catenin. An intracranial animal model was used to confirm that HOTAIR depletion inhibited GBM cell migration/invasion. In the orthotopic model, HOTAIR was required for GBM formation in vivo. In summary, HOTAIR is a potential therapeutic target in GBM.

No MeSH data available.


Related in: MedlinePlus