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Published on: October 27, 2020
KDM4A-driven SMAD5/TGFβ axis activation as a therapeutic target in cholangiocarcinoma: mechanistic insights and
Qi Wang1, Yiyang Kuai1, Fei Xiong1,2
1Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
Background:
Cholangiocarcinoma is a malignancy with poor prognosis and increasing incidence in recent years. Apart from early surgical resection, other treatments have shown limited efficacy. Lysine-specific demethylase 4A (KDM4A), a histone demethylase, is known to have a promotional effect on a variety of tumours. However, its impact on cholangiocarcinoma remains underexplored.
Methods:
The expression differences of KDM4A in cholangiocarcinoma and adjacent tissues were analyzed by database and tissue microarray. The effects of KDM4A on the growth and proliferation ability of cholangiocarcinoma cells were explored through subcutaneous tumor formation experiments in nude mice and cholangiocarcinoma mouse models. The regulatory role of KDM4A on TGFβ pathway was analyzed by real-time quantitative PCR and Western blot experiments. Bioinformatics methods were employed to predict KDM4A binding, which was validated by chromatin immunoprecipitation.
Results:
KDM4A was highly expressed in cholangiocarcinoma tissues compared with normal tissues, and KDM4A significantly promoted the proliferation and invasion ability of cholangiocarcinoma. KDM4A positively regulated SMAD5, upregulating its expression and subsequently promoting the expression of TGFβ pathway target genes ID1 and ID2. Knockdown of SMAD5 could reverse the biological effects caused by KDM4A. The expression of SMAD5 was regulated by the histone methylation mark H3K9me3. KDM4A was enriched at the SMAD5 gene promoter region, downregulated H3K9me3 marks, and thus promoted SMAD5 transcription. KDM4A inhibitor can inhibit the proliferation and invasive ability of cholangiocarcinoma through the aforementioned mechanisms. Treatment of cholangiocarcinoma model mice with a KDM4A inhibitor resulted in significantly reduced liver volume and lesion area in the treatment group compared to the control group.
Conclusion:
In summary, KDM4A promotes the development of cholangiocarcinoma by regulating SMAD5 to activate the TGFβ pathway. The KDM4A inhibitor JIB-04 shows potential in inhibiting cholangiocarcinoma progression, providing a rationale for the epigenetic therapy of cholangiocarcinoma.
Insights
Lysine-specific demethylase 4A (KDM4A) promotes cholangiocarcinoma growth by activating the TGFβ pathway via SMAD5. KDM4A inhibition offers a potential epigenetic therapy for this malignancy.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Cholangiocarcinoma (CCA) is an aggressive malignancy with increasing incidence and limited treatment options.
- Lysine-specific demethylase 4A (KDM4A), a histone demethylase, is implicated in various cancers but its role in CCA is largely unknown.
Purpose of the Study:
- To investigate the role of KDM4A in cholangiocarcinoma development and progression.
- To explore the potential of KDM4A inhibition as a therapeutic strategy for CCA.
Main Methods:
- Analysis of KDM4A expression in CCA tissues using databases and tissue microarrays.
- In vivo and in vitro experiments assessing KDM4A's impact on CCA cell proliferation and invasion.
- Investigating KDM4A's regulation of the TGFβ pathway via qPCR, Western blot, and chromatin immunoprecipitation.
Main Results:
- KDM4A is highly expressed in CCA and promotes tumor cell proliferation and invasion.
- KDM4A upregulates SMAD5 expression, activating the TGFβ pathway and promoting CCA.
- KDM4A inhibition significantly reduces CCA growth and lesion area in preclinical models.
Conclusions:
- KDM4A drives CCA progression by activating the SMAD5/TGFβ pathway.
- KDM4A inhibition, exemplified by JIB-04, demonstrates therapeutic potential for CCA.
- Targeting KDM4A represents a promising epigenetic therapy strategy for cholangiocarcinoma.
