Sooreshjani Moloud A, Nikhil Kumar, Kamra Mohini, Nguyen Dung N, Kumar Dinesh, Shah Kavita
Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA.
Cancers (Basel). 2021 May 12;13(10):2324. doi: 10.3390/cancers13102324.
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.
NKX3.1的下调与前列腺癌（PCa）的起始、进展及去势抵抗性前列腺癌（CRPC）的发展密切相关。然而，在PCa组织中，NKX3.1蛋白水平与mRNA水平之间存在明显差异，这表明其翻译后水平的调控起着至关重要的作用。本研究确定了NKX3.1与LIMK2之间存在强烈的负相关关系，而LIMK2在CRPC发病机制中至关重要。我们发现，LIMK2通过直接磷酸化使NKX3.1降解，这对于促进CRPC细胞及体内的致癌性至关重要。LIMK2还下调NKX3.1的mRNA水平。反过来，NKX3.1促进LIMK2的泛素化。因此，LIMK2 - NKX3.1之间的负向相互作用调节雄激素受体（AR）、ARv7和蛋白激酶B（AKT）信号通路，促进侵袭性表型。我们还发现了NKX3.1与磷酸酶和张力蛋白同源物（PTEN）之间的新联系，二者均被LIMK2下调。PTEN缺失与NKX3.1下调密切相关。由于NKX3.1是一种前列腺特异性肿瘤抑制因子，通过抑制LIMK2来维持其水平为开发CRPC的靶向治疗提供了巨大机遇。此外，由于NKX3.1下调AR转录并抑制AKT信号通路，通过抑制LIMK2来恢复其水平有望通过同时靶向两条驱动通路而特别有益，这是开发有效的PCa治疗方法的高度理想的必要条件。
