Protein Kinase D3 promotes the cell proliferation by activating the ERK1/c-MYC axis in breast cancer
Protein Kinase D3 promotes the cell proliferation by activating the ERK1/c-MYC axis in breast cancer
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蛋白激酶 D3 通过激活乳腺癌中的 ERK1/c-MYC 轴促进细胞增殖
DOI：
10.1111/jcmm.14772
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发表时间：
2020-01-16
影响因子：
5.3
通讯作者：
Chen, Liming
中科院分区：
文献类型：
--
作者：
Liu, Yan;Song, Hang;Chen, Liming
乳腺癌是所有妇女癌症死亡的第二大死因。先前的研究表明蛋白激酶D3（PRKD 3）参与乳腺癌的进展。此外，PRKD 3在三阴性乳腺癌组织中的蛋白水平高于正常乳腺组织。然而，PRKD 3在乳腺癌中的致癌机制尚未得到充分研究。多组学数据显示，ERK 1/c-MYC轴被鉴定为PRKD 3介导的下游通路的主要枢纽。我们的研究为PRKD 3/ERK 1/c-MYC通路在乳腺癌进展中发挥重要作用提供了证据。我们发现，通过CRISPR/Cas9基因组工程技术敲除PRKD 3抑制了ERK 1和c-MYC的磷酸化，但没有下调ERK 1/2表达或ERK 2的磷酸化。ERK 1和c-MYC磷酸化的抑制进一步导致乳腺癌细胞中c-MYC蛋白水平的降低，进而降低c-MYC靶基因的表达。我们还发现，PRKD 3的缺失降低了体外细胞增殖和体内肿瘤生长的速率，而PRKD 3敲除乳腺细胞中PRKD 3、ERK 1或c-MYC的异位（过）表达逆转了对细胞增殖和肿瘤生长的抑制。总的来说，我们的数据强烈地表明PRKD 3可能通过激活ERK 1-c-MYC轴促进乳腺癌细胞中的细胞增殖。
Breast cancer is the second leading death cause of cancer death for all women. Previous study suggested that Protein Kinase D3 (PRKD3) was involved in breast cancer progression. In addition, the protein level of PRKD3 in triple-negative breast adenocarcinoma was higher than that in normal breast tissue. However, the oncogenic mechanisms of PRKD3 in breast cancer is not fully investigated. Multi-omic data showed that ERK1/c-MYC axis was identified as a major pivot in PRKD3-mediated downstream pathways. Our study provided the evidence to support that the PRKD3/ERK1/c-MYC pathway play an important role in breast cancer progression. We found that knocking out PRKD3 by performing CRISPR/Cas9 genome engineering technology suppressed phosphorylation of both ERK1 and c-MYC but did not down-regulate ERK1/2 expression or phosphorylation of ERK2. The inhibition of ERK1 and c-MYC phosphorylation further led to the lower protein level of c-MYC and then reduced the expression of the c-MYC target genes in breast cancer cells. We also found that loss of PRKD3 reduced the rate of the cell proliferation in vitro and tumour growth in vivo, whereas ectopic (over)expression of PRKD3, ERK1 or c-MYC in the PRKD3-knockout breast cells reverse the suppression of the cell proliferation and tumour growth. Collectively, our data strongly suggested that PRKD3 likely promote the cell proliferation in the breast cancer cells by activating ERK1-c-MYC axis.