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Investigating Target Gene Function in a CD40 Agonistic Antibody-induced Colitis Model using CRISPR/Cas9-based Technologies
Published on: June 2, 2021
Deubiquitinating enzyme JOSD2 modulates cGAS to facilitate immune evasion in colorectal cancer
Jiamin Du1, Yiqun Fan2, Junwei Fu1
1Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Abstract:
Colorectal cancer (CRC) remains a formidable clinical challenge, many patients exhibit limited responses to conventional chemotherapy and targeted therapies. Although immunotherapy has demonstrated potential, its efficacy is largely restricted to a subset of patients with high microsatellite instability (MSI-H), highlighting the critical need to identify key molecular drivers of immune evasion in CRC. Through comprehensive bioinformatic analysis, we identified the deubiquitinating enzyme JOSD2 as a key player in CRC progression, with elevated expression correlating with poor prognosis in MSI-H patients (HR = 4.79, 95% CI: 3.6-7.96) and dysregulation of multiple immune-related pathways. Mechanistically, we discovered that JOSD2 suppresses cGAS enzymatic activity by removing K27-linked ubiquitination, thereby promoting M2 polarization of macrophages, a process critical for immunosuppression in the tumor microenvironment. Furthermore, using the JOSD2 catalytic inhibitor HY041004, we demonstrated both in vitro and in vivo that the inhibition of JOSD2 activated the cGAS-STING signaling pathway, leading to robust anti-tumor effects in CRC. These findings not only uncover a novel immunomodulatory mechanism in colorectal cancer but also provide a therapeutic rationale for the development of JOSD2-targeted anticancer strategies.
Insights
Colorectal cancer (CRC) immunotherapy is limited. We found JOSD2 drives immune evasion by suppressing cGAS activity, promoting tumor growth. Inhibiting JOSD2 restores anti-tumor immunity in CRC.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Colorectal cancer (CRC) presents significant treatment challenges, with limited efficacy of current therapies.
- Immunotherapy shows promise but is mainly effective in a subset of patients with high microsatellite instability (MSI-H).
- Identifying mechanisms of immune evasion is crucial for improving CRC treatment outcomes.
Purpose of the Study:
- To identify key molecular drivers of immune evasion in colorectal cancer.
- To elucidate the role of the deubiquitinating enzyme JOSD2 in CRC progression and immune response.
- To evaluate the therapeutic potential of targeting JOSD2 in CRC.
Main Methods:
- Comprehensive bioinformatic analysis to identify key molecular players in CRC.
- Investigation of JOSD2 expression and its correlation with prognosis in MSI-H CRC patients.
- Mechanistic studies on JOSD2's interaction with cGAS and its effect on macrophage polarization.
- In vitro and in vivo evaluation of a JOSD2 catalytic inhibitor (HY041004).
Main Results:
- Elevated JOSD2 expression is linked to poor prognosis in MSI-H CRC patients.
- JOSD2 suppresses cGAS enzymatic activity via K27-linked ubiquitination, promoting M2 macrophage polarization and immunosuppression.
- Inhibition of JOSD2 by HY041004 activates the cGAS-STING pathway.
- JOSD2 inhibition demonstrates significant anti-tumor effects in CRC models.
Conclusions:
- JOSD2 is a novel immunomodulatory factor in colorectal cancer progression.
- JOSD2 promotes tumor immune evasion by inhibiting the cGAS-STING pathway and driving M2 macrophage polarization.
- Targeting JOSD2 with inhibitors like HY041004 represents a promising therapeutic strategy for CRC.
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