A Constitutive Intrinsic Inflammatory Signaling Circuit Composed of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Cancer Castration Resistance

Androgen deprivation therapy is the most effective treatment for advanced prostate cancer, but almost all cancer eventually becomes castration resistant, and the underlying mechanisms are largely unknown. Here, we show that an intrinsic constitutively activated feedforward signaling circuit composed of IκBα/NF-κB(p65), miR-196b-3p, Meis2, and PPP3CC is formed during the emergence of castration-resistant prostate cancer (CRPC). This circuit controls the expression of stem cell transcription factors that drives the high tumorigenicity of CRPC cells. Interrupting the circuit by targeting its individual components significantly impairs the tumorigenicity and CRPC development. Notably, constitutive activation of IκBα/NF-κB(p65) in this circuit is not dependent on the activation of traditional IKKβ/NF-κB pathways that are important in normal immune responses. Therefore, our studies present deep insight into the bona fide mechanisms underlying castration resistance and provide the foundation for the development of CRPC therapeutic strategies that would be highly efficient while avoiding indiscriminate IKK/NF-κB inhibition in normal cells. [Display omitted] •A constitutive signaling circuit drives the high tumorigenicity of CRPC cells•The constitutive signaling circuit is composed of miR-196b, Meis2, PPP3CC, and p65•Targeting individual components of the signaling circuit inhibits CRPC development•Constitutive p65 activation in circuit is independent of traditional NF-κB pathways Jeong et al. identify a constitutively activated feedforward circuit composed of IκBα/NF-κB(p65), miR-196b-3p, Meis2, and PPP3CC formed during and required for castration-resistant prostate cancer (CRPC) development. Constitutive activation of this circuit is independent of traditional IKKβ/NF-κB pathways, suggesting that targeting this circuit could be important for CRPC treatment.