FEN1 mediates miR‐200a methylation and promotes breast cancer cell growthviaMET and EGFR signaling

Abstract

Flap endonuclease 1 (FEN1) is recognized as a pivotal factor in DNA replication, long‐patch excision repair, and telomere maintenance. Excessive FEN1 expression has been reported to be closely associated with cancer progression, but the specific mechanism has not yet been explored. In the present study, we demonstrated that FEN1 promoted breast cancer cell proliferation via an epigenetic mechanism of FEN1‐mediated up‐regulation of DNA methyltransferase (DNMT)1 and DNMT3a. FEN1 was proved to interact with DNMT3a through proliferating cell nuclear antigen (PCNA) to suppress microRNA (miR)‐200a‐5p expression mediated by methylation. Furthermore, miR‐200a‐5p was identified to repress breast cancer cell proliferation by inhibiting the expression of its target genes, hepatocyte growth factor (MET), and epidermal growth factor receptor (EGFR). Overall, our data surprisingly demonstrate that FEN1 promotes breast cancer cell growth via the formation of FENl/PCNA/DNMT3a complex to inhibit miR‐200a expression by DNMT‐mediated methylation and to recover the target genes expression of miR‐200a, MET, and EGFR. The novel epigenetic mechanism of FEN1 on proliferation promotion provides a significant clue that FEN1 might serve as a predictive biomarker and therapeutic target for breast cancer.—Zeng, X., Qu, X., Zhao, C., Xu, L., Hou, K., Liu, Y., Zhang, N., Feng, J., Shi, S., Zhang, L., Xiao, J., Guo, Z., Teng, Y., Che, X. FEN1 mediates miR‐200a methylation and promotes breast cancer cell growth via MET and EGFR signaling. FASEB J. 33, 10717–10730 (2019). http://www.fasebj.org

Biological and clinical significance of flap endonuclease‑1 in triple‑negative breast cancer: Support of metastasis and a poor prognosis

“…However, due to the complex mechanism of TNBC metastasis, some aspects remain unknown. FEN1 has been identified as a potential biomarker from previous studies, which found that overexpression of FEN1 could disrupt the cell cycle and promote cell proliferation in numerous types of cancer, including breast cancer ( 13 , 24 , 35 , 36 ). Furthermore, FEN1 overexpression was also associated with resistance to chemotherapy ( 18 , 22 ), and targeted therapy ( 37 ).…”

“…Virus production and FEN1-related infection were performed as described previously ( 24 ). In brief, the lentiviral vectors LV-GFP-FEN1-RNAi, LV-GFP-FEN1-3FLAG and empty vector controls were synthesized (Genechem Company).…”

“…Flap endonuclease-1 (FEN1) plays critical roles in both DNA replication and repair, by participating in the maturation of the Okazaki fragment, rescuing stalled replication forks, maintaining telomere stability and DNA long-patch base excision repair ( 8 – 10 ). An increasing amount of evidence shows that the overexpression of FEN1 in several types of tumor affects the proliferation, apoptosis, and drug resistance of tumor cells, which was also associated with poor prognosis ( 9 , 11 – 24 ). In addition, previous research showed that FEN1 mediated microRNA-200a methylation to promote breast cancer cell growth via the MET and EGFR signaling pathway ( 24 ).…”

“…An increasing amount of evidence shows that the overexpression of FEN1 in several types of tumor affects the proliferation, apoptosis, and drug resistance of tumor cells, which was also associated with poor prognosis ( 9 , 11 – 24 ). In addition, previous research showed that FEN1 mediated microRNA-200a methylation to promote breast cancer cell growth via the MET and EGFR signaling pathway ( 24 ). However, the function and molecular mechanisms of FEN1 in metastasis, particularly in highly invasive TNBC, has not been investigated.…”

Positive Cross-Talk Between CXC Chemokine Receptor 4 (CXCR4) and Epidermal Growth Factor Receptor (EGFR) Promotes Gastric Cancer Metastasis via the Nuclear Factor kappa B (NF-kB)-Dependent Pathway

“…Total cellular RNA was isolated with TRIzol reagent (Takara Bio, Kusatsu, Japan) according to the manufacturer’s instructions. Referring to our previous method [ 12 ]. PCR conditions were 95°C for 30 seconds; 45 cycles at 95°C for 5 seconds and 58°C for 34 seconds.…”