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CTCF promotes colorectal cancer cell proliferation and chemotherapy resistance to 5-FU via the P53-Hedgehog axis.

ABSTRACT: CTCF is overexpressed in several cancers and plays crucial roles in regulating aggressiveness, but little is known about whether CTCF drives colorectal cancer progression. Here, we identified a tumor-promoting role for CTCF in colorectal cancer. Our study demonstrated that CTCF was upregulated in colorectal cancer specimens compared with adjacent noncancerous colorectal tissues. The overexpression of CTCF promoted colorectal cancer cell proliferation and tumor growth, while the opposite effects were observed in CTCF knockdown cells. Increased GLI1, Shh, PTCH1, and PTCH2 levels were observed in CTCF-overexpressing cells using western blot analyses. CCK-8 and apoptosis assays revealed that 5-fluorouracil chemosensitivity was negatively associated with CTCF expression. Furthermore, we identified that P53 is a direct transcriptional target gene of CTCF in colorectal cancer. Western blot and nuclear?extract assays showed that inhibition of P53 can counteract Hedgehog signaling pathway repression induced by CTCF knockdown. In conclusion, we uncovered a crucial role for CTCF regulation that possibly involves the P53-Hedgehog axis and highlighted the clinical utility of colorectal cancer-specific potential therapeutic target as disease progression or clinical response biomarkers.

SUBMITTER: Lai Q

PROVIDER: S-EPMC7485712 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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CTCF promotes colorectal cancer cell proliferation and chemotherapy resistance to 5-FU via the P53-Hedgehog axis.

Lai Qiuhua Q Li Qingyuan Q He Chengcheng C Fang Yuxin Y Lin Simin S Cai Jianqun J Ding Jian J Zhong Qian Q Zhang Yue Y Wu Changjie C Wang Xinke X He Juan J Liu Yongfeng Y Yan Qun Q Li Aimin A Liu Side S

Aging 20200720 16

CTCF is overexpressed in several cancers and plays crucial roles in regulating aggressiveness, but little is known about whether CTCF drives colorectal cancer progression. Here, we identified a tumor-promoting role for CTCF in colorectal cancer. Our study demonstrated that CTCF was upregulated in colorectal cancer specimens compared with adjacent noncancerous colorectal tissues. The overexpression of CTCF promoted colorectal cancer cell proliferation and tumor growth, while the opposite effects ...[more]

PMID: 32688344

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Project description:Various studies have revealed that the Hedgehog (Hh) signaling pathway promotes ovarian cancer invasion, migration and drug resistance. Previous studies by our group have identified a set of genes, including multidrug resistance gene 1 (MDR1), that are regulated by Hh signaling in ovarian cancer. However, the association between Hh signaling activation and MDR1 expression requires further validation. In the present study, reverse transcription‑quantitative PCR or western blot assays were used to evaluate the mRNA and protein expression levels of MDR1, Sonic Hh (Shh), glioma‑associated oncogene 2 (Gli2), Gli1 and γ‑phosphorylated H2A.X variant histone (γ‑H2AX). MTT and colony‑formation assays were performed to determine the effect of cisplatin (DDP) after inhibiting the Hh pathway in ovarian cancer cells. The results indicated that MDR1, Gli2 and Shh levels were much higher in SK‑OV‑3 cells with acquired DDP resistance than in native SK‑OV‑3 cells. ES‑2 cells with overexpression of Gli2 were capable of efficiently forming colonies in the presence of low DDP concentrations. By contrast, Gli2 knockdown in SK‑OV‑3 cells decreased the colony‑forming ability under the same concentration of DDP. As determined by MTT assays, knockdown of Gli2 or targeting of the Hh signaling pathway with either Gli‑antagonist 61 (GANT61) or cyclopamine, in combination with DDP treatment, diminished the viability of ES‑2 and SK‑OV‑3 cells, whereas Gli2 overexpression increased the viability of ES‑2 cells in the presence of DDP. Knockdown of Gli2 or targeting the Hh signaling pathway with GANT61 also increased γ‑H2AX levels but decreased the expression of MDR1 in the presence of DDP. MDR1 expression is regulated by the Hh signaling pathway and is likely a downstream transcription factor of Gli2. In conclusion, targeting the Hh signaling pathway increases the sensitivity of ovarian cancer to DDP. MDR1 is a target gene of the Hh signaling pathway and this pathway may affect chemoresistance of ovarian cancer to DDP via MDR1.

Dataset Information

CTCF promotes colorectal cancer cell proliferation and chemotherapy resistance to 5-FU via the P53-Hedgehog axis.

Publications

CTCF promotes colorectal cancer cell proliferation and chemotherapy resistance to 5-FU via the P53-Hedgehog axis.

Similar Datasets

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