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Published on: January 22, 2021
Clinical and therapeutic significance of sirtuin-4 expression in colorectal cancer
Guoyu Huang1, Jun Cheng1, Fudong Yu2
1Department of Gastrointestinal Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.
Abstract:
Several members of the sirtuin family (SIRT1-7), which are a highly conserved family of NAD+-dependent enzymes, play an important role in tumor formation. Recent studies indicate that SIRT4 acts as a tumor suppressor by regulating glutamine metabolism. In the present study, we investigated the expression and activity of SIRT4 in colorectal cancer. Using a tissue microarray of 89 colorectal cancer cases, we found that SIRT4 was significantly downregulated in colorectal cancer tissues compared with that noted in the corresponding normal tissue (P<0.001). Lower SIRT4 levels were associated with worse pathological differentiation (P=0.031) and poorer post-operative overall survival rate (P=0.041). We found that SIRT4 overexpression inhibited the proliferation of colorectal cancer cells in vitro and in vivo. SIRT4 inhibited the glutamine metabolism of colorectal cancer cells and synergistically with glycolysis inhibitors induced cell death. SIRT4 also increased the sensitivity of colorectal cancer cells to chemotherapeutic drug 5-fluorouracil by inhibiting the cell cycle. Together, these results highlight the prognostic value of SIRT4 in colorectal cancer and the potential application of SIRT4 in colorectal cancer treatment.
Insights
Sirtuin 4 (SIRT4) is downregulated in colorectal cancer, acting as a tumor suppressor by inhibiting cell proliferation and glutamine metabolism. Lower SIRT4 levels indicate a poorer prognosis and potential therapeutic target for colorectal cancer.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Sirtuins (SIRT1-7) are NAD+-dependent enzymes involved in tumor formation.
- SIRT4 functions as a tumor suppressor, regulating glutamine metabolism.
- The role of SIRT4 in colorectal cancer requires further investigation.
Purpose of the Study:
- To investigate the expression and activity of SIRT4 in colorectal cancer.
- To determine the prognostic value of SIRT4 in colorectal cancer patients.
- To explore the therapeutic potential of SIRT4 in colorectal cancer treatment.
Main Methods:
- Analysis of SIRT4 expression in 89 colorectal cancer tissues using tissue microarrays.
- Correlation of SIRT4 levels with clinicopathological features and patient survival.
- In vitro and in vivo studies of SIRT4 overexpression on colorectal cancer cell proliferation.
- Investigation of SIRT4's effects on glutamine metabolism, cell death, and response to 5-fluorouracil.
Main Results:
- SIRT4 was significantly downregulated in colorectal cancer tissues compared to normal tissues (P<0.001).
- Lower SIRT4 levels correlated with worse pathological differentiation (P=0.031) and poorer overall survival (P=0.041).
- SIRT4 overexpression inhibited colorectal cancer cell proliferation, glutamine metabolism, and enhanced sensitivity to 5-fluorouracil by cell cycle inhibition.
Conclusions:
- SIRT4 exhibits tumor-suppressive functions in colorectal cancer.
- SIRT4 downregulation is a prognostic marker for poor outcomes in colorectal cancer.
- SIRT4 represents a potential therapeutic target for colorectal cancer treatment.
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