TRIB2 functions as novel oncogene in colorectal cancer by blocking cellular senescence through AP4/p21 signaling
Zhenlin Hou1, Kaixuan Guo1, Xuling Sun1
1Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
Background:
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. However, the role of TRIB2 in cellular senescence of colorectal cancer (CRC) and its molecular mechanism remains unclear.
Methods:
The 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.
Results:
We 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.
Conclusion:
These 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.
Insights
Tribbles homolog 2 (TRIB2) suppresses cellular senescence in colorectal cancer (CRC) by inhibiting p21 expression via AP4 interaction. Targeting TRIB2 may offer a new therapeutic strategy for CRC patients.
Area of Science:
- Oncology
- Cell Biology
- Molecular Mechanisms
Background:
- Cellular senescence is a key mechanism for tumor suppression.
- Tribbles homolog 2 (TRIB2) influences cancer cell proliferation and drug resistance.
- The role of TRIB2 in colorectal cancer (CRC) senescence and its underlying mechanisms are not well understood.
Purpose of the Study:
- To investigate the role of TRIB2 in cellular senescence of colorectal cancer.
- To elucidate the molecular mechanism by which TRIB2 regulates senescence in CRC.
- To evaluate TRIB2 as a potential therapeutic target for CRC.
Main Methods:
- Immunohistochemistry and RT-PCR to assess TRIB2 expression in CRC tissues.
- Cell Counting Kit-8, flow cytometry, and senescence-associated β-galactosidase staining to evaluate cellular senescence.
- Western blot, RT-PCR, luciferase assay, immunoprecipitation, and chromatin-immunoprecipitation to determine TRIB2's regulatory mechanism on p21 and AP4 interaction.
Main Results:
- TRIB2 expression is upregulated in CRC tissues and correlates with poor prognosis.
- TRIB2 depletion inhibits CRC cell proliferation and induces senescence, while TRIB2 overexpression promotes proliferation and blocks senescence.
- TRIB2 interacts with AP4, inhibiting p21 expression and consequently suppressing cellular senescence.
Conclusions:
- TRIB2 suppresses cellular senescence in CRC by interacting with AP4 to downregulate p21 expression.
- TRIB2 represents a potential therapeutic target for colorectal cancer treatment.
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