Abstract：
The Dickkopf family proteins (DKKs) are strong Wnt signaling antagonists that play a significant role in colorectal cancer (CRC) development and progression. Recent work has shown that DKKs, mainly DKK1, are associated with the induction of chemoresistance in CRC and that DKK1 expression in cancer cells correlates with that of protein arginine N-methyltransferase 5 (PRMT5). This points to the presence of a regulatory loop between DKK1 and PRMT5. Herein, we addressed the question of whether PRMT5 contributes to DKK1 expression in CRC and hence CRC chemoresistance. Both in silico and in vitro approaches were used to explore the relationship between PRMT5 and different DKK members. Our data demonstrated that DKK1 expression is significantly upregulated in CRC clinical samples, KRAS-mutated CRC in particular and that the levels of DKK1 positively correlate with PRMT5 activation. Chromatin immunoprecipitation (ChIP) data indicated a possible epigenetic role of PRMT5 in regulating DKK1, possibly through the symmetric dimethylation of H3R8. Knockdown of DKK1 or treatment with the PRMT5 inhibitor CMP5 in combination with doxorubicin yielded a synergistic anti-tumor effect in KRAS mutant, but not KRAS wild-type, CRC cells. These findings suggest that PRMT5 regulates DKK1 expression in CRC and that inhibition of PRMT5 modulates DKK1 expression in such a way that reduces CRC cell growth.
摘要：
Dickkopf家族蛋白（DKK）是强Wnt信号拮抗剂，在结直肠癌（CRC）的发展和进展中起重要作用。最近的工作表明，DKK，主要是DKK1与CRC中化学抗性的诱导有关，并且癌细胞中DKK1的表达与蛋白质精氨酸N-甲基转移酶5（PRMT5）的表达有关。这表明在DKK1和PRMT5之间存在调节环。在这里，我们解决了PRMT5是否有助于CRC中DKK1的表达以及CRC化学耐药的问题.使用计算机模拟和体外方法来探索PRMT5与不同DKK成员之间的关系。我们的数据表明，DKK1表达在CRC临床样本中显著上调，特别是KRAS突变的CRC，DKK1的水平与PRMT5激活呈正相关。染色质免疫沉淀（ChIP）数据表明PRMT5在调节DKK1中可能具有表观遗传作用，可能是通过H3R8的对称二甲基化。敲除DKK1或用PRMT5抑制剂CMP5与阿霉素联合治疗在KRAS突变体中产生了协同抗肿瘤作用，但不是KRAS野生型,CRC细胞。这些发现表明PRMT5调节CRC中的DKK1表达,并且PRMT5的抑制以减少CRC细胞生长的方式调节DKK1表达。
