Knockdown of FOXK1 alone or in combination with apoptosis-inducing 5-FU inhibits cell growth in colorectal cancer

Abstract

Forkhead box K1 (FOXK1) is a member of the FOX transcription factor family, which plays an important role in oncogenesis. However, the exact function and mechanism of FOXK1 in human colorectal cancers (CRCs) remain unclear. In the present study, we first screened for potential FOXK1 target genes by ectopically expressing FOXK1 in SW480 cells and examined the subsequent changes in the expression levels of major oncogenes using RT-PCR. We also evaluated the effects of FOXK1 regulation on growth and apoptosis. In addition, we investigated the biological impact of FOXK1 knockdown on CRC cells in vitro and in vivo. We found that FOXK1 overexpression increased the expression of multiple oncogenes in vitro. FOXK1 promoted serum-dependent and anchorage-dependent and -independent cell growth. Knockdown of FOXK1 induced G0/G1 cell cycle arrest in CRC cells. Moreover, FOXK1 suppression induced apoptosis and increased cell susceptibility to 5-fluorouracil (5-FU)-induced apoptosis. Furthermore, a xenograft model was established to explore FOXK1 shRNA-mediated tumorigenesis in vivo. A strong antitumorigenic effect of FOXK1-shRNA was enhanced when combined with 5-FU treatment. These findings implicate FOXK1 as a cell cycle and growth modulator that inhibits apoptosis in colon cancer cells. FOXK1-shRNA may serve as a novel and potent therapeutic agent, alone or with 5-FU, against colon cancer.

MiR-646 inhibited cell proliferation and EMT-induced metastasis by targeting FOXK1 in gastric cancer

“…The EMT is recognised as an important process that occurs during GC cell invasion ( Wu et al , 2016a , 2016b , 2016c , 2016d ; Yang et al , 2008 ). To determine whether miR-646 has a critical role in the GC EMT, we first examined cell morphology.…”

“…The EMT is reportedly induced by various signals in the tumour microenvironment, including TGF- β 1 ( Wu et al , 2016a , 2016b , 2016c , 2016d ; Hou et al , 2016 ). We first examined the miR-646 levels in TGF- β 1-treated BGC-823 and AGS cells.…”

“…Therefore, this study provides useful insights into the mechanisms underlying GC metastasis. The TGF- β signalling pathway has pivotal roles in diverse developmental processes and the pathogenesis of many diseases, including cancer ( Li et al , 2015 ; Peng et al , 2016 ; Wu et al , 2016a , 2016b , 2016c , 2016d ). Several studies have shown that miRNAs regulate downstream molecules of TGF- β to modulate the EMT.…”

“…Forkhead-box K1, a member of the FOX family of transcription factors, has been implicated in certain tumour types, including colorectal, gastric and ovarian tumours ( Ying et al , 2014 ; Peng et al , 2016 ; Wu et al , 2016a , 2016b , 2016c , 2016d ). Forkhead-box K1 has been shown to contribute to loss of the epithelial marker E-cadherin and upregulation of the expression of mesenchymal markers, including vimentin, and to promote tumour cell invasion ( Wu et al , 2016a , 2016b , 2016c , 2016d ). In the present study, we have demonstrated that miR-646 suppresses FOXK1 expression; we believe that FOXK1 contribute to the inhibitory effect of miR-646 on the EMT in GC.…”

Identification of potential key genes associated with diffuse large B-cell lymphoma based on microarray gene expression profiling

“…In our study, FOXK1 and CNOT6L, which were two crucial genes with a high connection degree in the integrated network of down-regulated genes, were predicted as the targeted genes of miR-17-5p. Myocyte nuclear factor (FOXK1) contains a fork head DNA binding domain which is correlative with cell growth and metabolism, and FOXK1 suppression lead to apoptosis and promote cell susceptibility to 5-fluorouracilinduced apoptosis in colorectal cancer cell [46]. In addition, CCR4-NOT transcription complex subunit 6 like (CNOT6L) is a deadenylase subunit of CCR4-NOT complex [47].…”