LIMK2-NKX3.1 Engagement Promotes Castration-Resistant Prostate Cancer

Abstract

NKX3.1’s downregulation is strongly associated with prostate cancer (PCa) initiation, progression, and CRPC development. Nevertheless, a clear disagreement exists between NKX3.1 protein and mRNA levels in PCa tissues, indicating that its regulation at a post-translational level plays a vital role. This study identified a strong negative relationship between NKX3.1 and LIMK2, which is critical in CRPC pathogenesis. We identified that NKX3.1 degradation by direct phosphorylation by LIMK2 is crucial for promoting oncogenicity in CRPC cells and in vivo. LIMK2 also downregulates NKX3.1 mRNA levels. In return, NKX3.1 promotes LIMK2’s ubiquitylation. Thus, the negative crosstalk between LIMK2-NKX3.1 regulates AR, ARv7, and AKT signaling, promoting aggressive phenotypes. We also provide a new link between NKX3.1 and PTEN, both of which are downregulated by LIMK2. PTEN loss is strongly linked with NKX3.1 downregulation. As NKX3.1 is a prostate-specific tumor suppressor, preserving its levels by LIMK2 inhibition provides a tremendous opportunity for developing targeted therapy in CRPC. Further, as NKX3.1 downregulates AR transcription and inhibits AKT signaling, restoring its levels by inhibiting LIMK2 is expected to be especially beneficial by co-targeting two driver pathways in tandem, a highly desirable requisite for developing effective PCa therapeutics.

LIMK2 Is a Novel Prognostic Biomarker and Correlates With Tumor Immune Cell Infiltration in Lung Squamous Cell Carcinoma

“…Meanwhile, the survival analysis also showed that high LIMK2 expression was associated with a better prognosis in LUSC, suggesting that LIMK2 may become a prognostic marker for LUSC. However, previous studies have demonstrated that LIMK2 is correlated with poor prognosis in many cancers, including bladder cancer ( 16 ), breast cancer ( 17 ), and prostate cancer ( 18 ). Both LIMK1 and LIMK2 belong to the LIMK family; despite their structural similarities, the LIMK1/LIMK2 may have different roles in cancer development and progression.…”

Enhancing Disease Risk Gene Discovery by Integrating Transcription Factor-Linked Trans-located Variants into Transcriptome-Wide Association Analyses

“…3; Table S9). Similarly, we also highlighted key TFs, NKX3-1 [62][63][64][65] and GATA2 [66][67][68][69] for prostate cancer (Table S10). Unfortunately, we did not observe significant TFs in lung cancer, likely due to the less genetic effects of the TF on downstream regulated genes 38 .…”

Fibroblast‐derived exosomal microRNA regulates NKX3‐1 expression in androgen‐sensitive, androgen receptor‐dependent prostate cancer cells

“…26,27 The NKX3-1 gene is an androgenregulated gene, and loss of NKX3-1 is strongly associated with progression to CRPC. 28 Using small-activating RNA technology, researchers showed that upregulation of NKX3-1 mRNA in LNCaP cells promotes the effectiveness of ADT by maintaining androgen dependency in PCa cells and by preventing progression to CRPC. 29 Our results showed that the mRNA expression of NKX3-1 in LNCaP cells (androgen-sensitive, AR-dependent cells) and E9 cells (showing low androgen sensitivity and AR dependence) but not in F10 cells (showing AR-V7 expression, low androgen sensitivity, and AR independence) and AIDL cells (androgen-insensitive, ARindependent cells) was significantly increased by treatment with the CMs derived from AR-activating factorsecreted fibroblast lines (PrSC and pcPrF-M5 cells).…”

“…NKX3‐1 is a gene that plays essential roles in the differentiation of the prostate glandular epithelium and is a marker of cancer cell differentiation 26,27 . The NKX3‐1 gene is an androgen‐regulated gene, and loss of NKX3‐1 is strongly associated with progression to CRPC 28 . Using small‐activating RNA technology, researchers showed that upregulation of NKX3‐1 mRNA in LNCaP cells promotes the effectiveness of ADT by maintaining androgen dependency in PCa cells and by preventing progression to CRPC 29 .…”