Reciprocal deregulation of NKX3.1 and AURKA axis in castration-resistant prostate cancer and NEPC models.
Reciprocal deregulation of NKX3.1 and AURKA axis in castration-resistant prostate cancer and NEPC models.
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DOI：
10.1186/s12929-021-00765-z
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发表时间：
2021-10-08
影响因子：
11
通讯作者：
Shah K
中科院分区：
文献类型：
--
作者：
Sooreshjani MA;Kamra M;Zoubeidi A;Shah K
NKX3.1是一种前列腺特异性肿瘤抑制因子，其基因组丢失或其蛋白水平严重下调，这总是与前列腺癌（PCa）的预后不良相关。然而，其mRNA和蛋白质水平之间存在明显的脱节，表明其翻译后调节可能是维持其蛋白质水平的关键。类似地，AURKA在前列腺癌（PCa）的所有阶段都过度表达，包括去势抵抗性PCa（CRPC）和神经内分泌PCa（NEPC），尽管其转录物仅在约15%的病例中增加，暗示了其他的失调机制。因此，鉴定控制AURKA和NKX3.1水平的上游调节物和/或其下游效应物提供了在高度致命的CRPC和NEPC中抑制AURKA和上调NKX3.1的替代途径。迄今为止，AURKA和NKX3.1在任何研究中都没有相互关联。化学遗传筛选显示NKX3.1是AURKA的直接靶点。在CRPC和NEPC细胞中使用几种生物化学技术分析AURKA-NKX 3.1串扰。我们在CRPC和NEPC细胞中发现了AURKA和NKX3.1之间的相互循环。我们观察到AURKA介导的NKX3.1下调是驱动CRPC发病和NEPC分化的主要机制。AURKA在三个位点磷酸化NKX3.1，使其降解，但AURKA不调节NKX3.1 mRNA水平。NKX3.1降解驱动细胞中高度侵袭性的致癌表型。NKX3.1还在反馈回路中降低了AURKA。因此，NKX3.1-AURKA环上调串联的AKT、ARv 7和雄激素受体（AR）信号传导，从而促进高度恶性表型。同样重要的是，我们观察到NKX3.1过表达完全消除了NEPC细胞中突触素和烯醇化酶的表达，揭示了NKX3.1和神经内分泌表型之间的强烈负相关性，这进一步证实了测量神经突生长。WT-NKX 3.1抑制神经元分化，而3A-NKX 3.1表达则使其消失，NKX 3. 1缺失可能是导致CRPC和NEPC中AURKA上调的主要机制，反之亦然。NKX3.1基因组丢失需要基因治疗，尽管如此，靶向AURKA提供了维持NKX3.1水平的强大工具。相反，当使用小分子的NKX3.1上调策略实现时，由于这些高度侵袭性的不治之症中的相互循环，AURKA抑制应该协同作用。在线版本包含补充材料，可通过10.1186/s12929-021-00765-z获得。
NKX3.1, a prostate-specific tumor suppressor, is either genomically lost or its protein levels are severely downregulated, which are invariably associated with poor prognosis in prostate cancer (PCa). Nevertheless, a clear disconnect exists between its mRNA and protein levels, indicating that its post-translational regulation may be critical in maintaining its protein levels. Similarly, AURKA is vastly overexpressed in all stages of prostate cancer (PCa), including castration-resistant PCa (CRPC) and neuroendocrine PCa (NEPC), although its transcripts are only increased in ~ 15% of cases, hinting at additional mechanisms of deregulation. Thus, identifying the upstream regulators that control AURKA and NKX3.1’s levels and/or their downstream effectors offer an alternative route to inhibit AURKA and upregulate NKX3.1 in highly fatal CRPC and NEPC. AURKA and NKX3.1 have not linked to each other in any study to date. A chemical genetic screen revealed NKX3.1 as a direct target of AURKA. AURKA-NKX3.1 cross-talk was analyzed using several biochemical techniques in CRPC and NEPC cells. We uncovered a reciprocal loop between AURKA and NKX3.1 in CRPC and NEPC cells. We observed that AURKA-mediated NKX3.1 downregulation is a major mechanism that drives CRPC pathogenesis and NEPC differentiation. AURKA phosphorylates NKX3.1 at three sites, which degrades it, but AURKA does not regulate NKX3.1 mRNA levels. NKX3.1 degradation drives highly aggressive oncogenic phenotypes in cells. NKX3.1 also degrades AURKA in a feedback loop. NKX3.1-AURKA loop thus upregulates AKT, ARv7 and Androgen Receptor (AR)-signaling in tandem promoting highly malignant phenotypes. Just as importantly, we observed that NKX3.1 overexpression fully abolished synaptophysin and enolase expression in NEPC cells, uncovering a strong negative relationship between NKX3.1 and neuroendocrine phenotypes, which was further confirmed be measuring neurite outgrowth. While WT-NKX3.1 inhibited neuronal differentiation, 3A-NKX3.1 expression obliterated it. NKX3.1 loss could be a major mechanism causing AURKA upregulation in CRPC and NEPC and vice versa. NKX3.1 genomic loss requires gene therapy, nonetheless, targeting AURKA provides a powerful tool to maintain NKX3.1 levels. Conversely, when NKX3.1 upregulation strategy using small molecules comes to fruition, AURKA inhibition should work synergistically due to the reciprocal loop in these highly aggressive incurable diseases. The online version contains supplementary material available at 10.1186/s12929-021-00765-z.
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影响因子：
8.8
作者：
Bowen C;Ju JH;Lee JH;Paull TT;Gelmann EP
通讯作者：
Gelmann EP
影响因子：
4
作者：
Johnson, Emmanuel O.;Chang, Kuei-Hua;Shah, Kavita
通讯作者：
Shah, Kavita
影响因子：
2.8
作者：
Gelmann, EP;Bowen, C;Bubendorf, L
通讯作者：
Bubendorf, L
影响因子：
45.3
作者：
DuBois, Steven G.;Marachelian, Araz;Mosse, Yael P.
通讯作者：
Mosse, Yael P.
DOI：
10.1158/1541-7786.mcr-12-0025
发表时间：
2012-06
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Kwon YW;Kim IJ;Wu D;Lu J;Stock WA Jr;Liu Y;Huang Y;Kang HC;DelRosario R;Jen KY;Perez-Losada J;Wei G;Balmain A;Mao JH
通讯作者：
Mao JH