Abstract
BackgroundCellular senescence is a state of irreversible cell growth arrest and senescence cells permanently lose proliferation potential. Induction of cellular senescence might be a novel therapy for cancer cells. TRIB2 has been reported to participate in regulating proliferation and drug resistance of various cancer cells. However, the role of TRIB2 in cellular senescence of colorectal cancer (CRC) and its molecular mechanism remains unclear.MethodsThe expression of TRIB2 in colorectal cancer tissues and adjacent tissues was detected by immunohistochemistry and RT-PCR. The growth, cell cycle distribution and cellular senescence of colorectal cancer cells were evaluated by Cell Counting Kit-8 (CCK8) assay, flow cytometry detection and senescence-associated β-galactosidase staining, respectively. Western blot, RT-PCR and luciferase assay were performed to determine how TRIB2 regulates p21. Immunoprecipitation (IP) and chromatin-immunoprecipitation (ChIP) were used to investigate the molecular mechanisms.ResultsWe found that TRIB2 expression was elevated in CRC tissues compared to normal adjacent tissues and high TRIB2 expression indicated poor prognosis of CRC patients. Functionally, depletion of TRIB2 inhibited cancer cells proliferation, induced cell cycle arrest and promoted cellular senescence, whereas overexpression of TRIB2 accelerated cell growth, cell cycle progression and blocked cellular senescence. Further studies showed that TRIB2 physically interacted with AP4 and inhibited p21 expression through enhancing transcription activities of AP4. The rescue experiments indicated that silencing of AP4 abrogated the inhibition of cellular senescence induced by TRIB2 overexpression.ConclusionThese data demonstrate that TRIB2 suppresses cellular senescence through interaction with AP4 to down-regulate p21 expression. Therefore, TRIB2 could be a potential target for CRC treatment.
Highlights
Cellular senescence is a state of irreversible cell growth arrest and senescence cells permanently lose proliferation potential
Tribbles pseudokinase 2 (TRIB2) is overexpressed in colorectal cancer It has been reported that TRIB2 is amplified in human acute myeloid leukemia (AML) as well as other solid tumors [10, 24]
(See figure on previous page.) Fig. 5 TRIB2 regulates cell proliferation and cellular senescence dependent on activating enhancer-binding protein 4 (AP4). a Western blot analysis of TRIB2, AP4 and p21 expression in SW48 and LoVo cells transfected with TRIB2-expressing plasmid and or not AP4-specific Short interfering RNA (siRNA). b mRNA expression of p21 in SW48 and LoVo cells transfected with TRIB2-expressing plasmid and or not AP4-specific siRNA. c p21-Luc was co-transfected with TRIB2-expressing plasmid and or not AP4-specific siRNA into SW48 and LoVo cells
Summary
Cellular senescence is a state of irreversible cell growth arrest and senescence cells permanently lose proliferation potential. Induction of cellular senescence might be a novel therapy for cancer cells. TRIB2 has been reported to participate in regulating proliferation and drug resistance of various cancer cells. The role of TRIB2 in cellular senescence of colorectal cancer (CRC) and its molecular mechanism remains unclear. Tribbles homolog 2, a member of the tribbles family (TRIB1, TRIB2, TRIB3), is first identified in Drosophila as mitosis blocker that regulates embryo and germ cell development [1]. It comprises an N-terminal domain, a C-terminal domain, and a central pseudokinase domain that contains a Ser/Thr protein kinase-like domain but. Senescence might be a promising target for tumor therapy
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