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RSK2 phosphorylates T-bet to attenuate colon cancer metastasis and growth
Ke Yao1,2, Cong Peng1,3, Yuwen Zhang1
1The Hormel Institute, University of Minnesota, Austin, MN 55912.
Abstract:
Metastasis is a major cause of cancer-related deaths. Approximately 80% of patients with colorectal cancer develop liver metastasis and 20% develop lung metastasis. We found that at different stages of colon cancer, IFNγ secretion from peripheral blood mononuclear cells was decreased compared with healthy controls. The ribosomal S6 kinase (RSK) family of kinases has multiple cellular functions, and we examined their roles in this observed IFNγ decrease. Flow cytometry analysis of wild-type (WT) and RSK2 knockout (KO) mice revealed significantly lower levels of IFNγ in the RSK2 KO mice compared with the WT mice. Since IFNγ is a component of immunity, which contributes to protection against metastatic carcinomas, we conducted a colon cancer liver metastasis experiment. We found significantly greater metastasis in RSK2 KO mice compared with WT mice. Transcription factor T-bet can directly activate Ifnγ gene transcription. In vitro kinase assay results showed that RSK2 phosphorylated T-bet at serines 498 and 502. We show that phosphorylation of T-bet by RSK2 is required for IFNγ expression, because knockdown of RSK2 expression or overexpression of mutant T-bet reduces IFNγ mRNA expression. To verify the function of the phosphorylation sites, we overexpressed a constitutively active mutant T-bet (S498E/S502E) in bone marrow. Mutant T-bet restored the IFNγ mRNA levels and dramatically reduced the metastasis rate in these mice. Overall, these results indicate that phosphorylation of T-bet is required for the inhibition of colon cancer metastasis and growth through a positive regulation of RSK2/T-bet/IFNγ signaling.
Insights
This study reveals that ribosomal S6 kinase 2 (RSK2) activates interferon gamma (IFNγ) by phosphorylating T-bet, which is crucial for inhibiting colon cancer metastasis. RSK2/T-bet/IFNγ signaling is key to controlling tumor spread.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Metastasis is a primary driver of cancer mortality, particularly in colorectal cancer with high rates of liver and lung metastasis.
- Reduced interferon gamma (IFNγ) secretion is observed in colon cancer patients, suggesting a compromised immune response.
- The ribosomal S6 kinase (RSK) family's role in IFNγ regulation during cancer progression was investigated.
Purpose of the Study:
- To investigate the role of RSK2 in regulating IFNγ production in the context of colon cancer.
- To determine if RSK2-mediated phosphorylation of transcription factor T-bet influences IFNγ expression and colon cancer metastasis.
- To explore the therapeutic potential of the RSK2/T-bet/IFNγ signaling pathway in inhibiting colon cancer growth and metastasis.
Main Methods:
- Flow cytometry was used to compare IFNγ levels in wild-type (WT) and RSK2 knockout (KO) mice.
- In vitro kinase assays were performed to identify RSK2 phosphorylation sites on T-bet.
- Gene knockdown and overexpression of T-bet mutants were utilized to assess the impact on IFNγ mRNA expression and metastasis rates in mice.
Main Results:
- RSK2 knockout mice exhibited significantly lower IFNγ levels and increased liver metastasis compared to WT mice.
- RSK2 was found to phosphorylate T-bet at serines 498 and 502, a modification essential for IFNγ gene transcription.
- Overexpression of a constitutively active T-bet mutant (S498E/S502E) restored IFNγ mRNA levels and significantly reduced metastasis in RSK2 KO mice.
Conclusions:
- RSK2-mediated phosphorylation of T-bet is a critical regulatory step for IFNγ expression.
- The RSK2/T-bet/IFNγ signaling axis plays a significant role in suppressing colon cancer metastasis and growth.
- Targeting this pathway holds promise for developing novel therapeutic strategies against metastatic colorectal cancer.
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