Defining the mechanism of STAT3 regulation by ABI1 in prostate cancer
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Author
Li, XiangTerm and Year
Summer 2023Date Published
2023-07
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Show full item recordAbstract
Prostate cancer, driven by hormones and the androgen receptor (AR), initially responds to AR pathway-targeted treatments. However, tumor relapse arises from a process called the prostate cancer cell lineage switch. This switch involves transcriptional and epigenetic reprogramming, allowing cancer cells to acquire a new identity and bypass the stress caused by anti-AR treatments, resulting in increased proliferation and metastasis. Our study delves into the regulatory mechanism of STAT3, a key modulator, by the tumor suppressor ABI1 during the process of lineage switch. We observed an inverse correlation between ABI1 expression and the progression of the lineage switch. Using tumor models, we demonstrated that ABI1 modulates the phosphorylation of STAT3 by regulating kinase activities. Additionally, we discovered that ABI1 interacts with DNA through unique intrinsic disordered DNA binding regions. Notably, during prostate cancer lineage switch, a specific ABI1 EXON4 undergoes abnormal splicing, enhancing the ABI1-DNA interaction and influencing epigenetic remodeling by modulating chromatin accessibility. Our findings highlight the role of ABI1 in regulating STAT3 activities through its DNA interaction and reveal a reciprocal regulation between ABI1 and STAT3 in terms of nuclear localization, thereby influencing the lineage switch driven by STAT3. Overall, we propose that ABI1 acts as a master regulator of the lineage switch by maintaining the homeostasis of epigenetic and transcriptional processes.Collections
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