Overexpression of N-terminal kinase like gene promotes tumorigenicity of hepatocellular carcinoma by regulating cell cycle progression and cell motility

Abstract

Amplification and overexpression of CHD1L is one of the most frequent genetic alterations in hepatocellular carcinoma (HCC). Here we found that one of CHD1L downstream targets, NTKL, was frequently upregulated in HCC, which was significantly correlated with vascular invasion (P = 0.012) and poor prognosis (P = 0.050) of HCC. ChIP assay demonstrated the binding of CHD1L to the promoter region of NTKL. QRT-PCR study showed that the expression of NTKL positively correlated with CHD1L expression in both clinical samples and cell lines. Functional study found that NTKL had strong oncogenic roles, including increased cell growth, colony formation in soft agar, and tumor formation in nude mice. Further study found that NTKL could promote G1/S transition by decreasing P53 and increasing CyclinD1 expressions. NTKL overexpression could accelerate the mitotic exit and chromosome segregation, which led to the cytokinesis failure and subsequently induced apoptosis. NTKL also regulated cell motility by facilitating philopodia and lamellipodia formation through regulating F-actin reorganization and the phosphorylation of small GTPase Rac1/cdc42. Using co-IP and mass spectrometry approach, we identified the large GTPase dynamin2 as an interacting protein of NTKL, which might be responsible for the phenotype alterations caused by NTKL overexpression, such as cytokinesis failure, increased cell motility and abnormal of cell division.

KCTD12 promotes tumorigenesis by facilitating CDC25B/CDK1/Aurora A-dependent G2/M transition

“…Cell cycle dysregulation is a common feature of human cancers that leads to at least two hallmarks of cancer development, namely, uncontrolled cell proliferation and genomic and chromosomal instability. 1 , 2 , 3 It is well established that proper progression through the cell cycle is monitored by members of the cyclin-dependent kinase (CDK) family, whose activity is regulated by specific activators (cyclins) and inhibitors (Ink4 and Cip/Kip family members). 4 Constitutive CDK activation causes a significant change in protein phosphorylation and drives tumor cell cycle progression, which results in unscheduled cell proliferation and tumorigenicity.…”

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

“…Activated FOXO3a disturbed the interaction between β-catenin and TCF and inhibited the expression of β-catenin/TCF target genes CyclinD1[ 24 ]. NTKL overexpression could accelerate the mitotic exit and chromosome segregation, which could promote G1/S transition by decreasing P53 and increasing CyclinD1 expressions [ 25 ].…”

Prognostic role of chromodomain helicase DNA binding protein 1-like protein in human solid cancers

“…[ 25 – 27 ] Kazal-like domains proteoglycan 1 and N-terminal kinase like, as 2 of CHD1L targets, upregulated or activated by CHD1L, participated in tumorigenicity of HCC. [ 28 , 29 ] Additionally, a novel molecular pathway, CHD1L/TCTP/Cdc25C/Cdk1, was demonstrated to induce mitotic defects and chromosome missegregation in HCC development. [ 30 ] Researcher also found that CHD1L showed a strong oncogenic ability in CRC, the overexpression of which could promote tumor progression by promoting G1/S-phase cells and inhibiting apoptosis in CRC.…”