Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
Cell Death Dis. 2022 May 2;13(5):424. doi: 10.1038/s41419-022-04877-8.
UHMK1, a serine/threonine kinase with a U2AF homology motif, is implicated in RNA processing and protein phosphorylation. Increasing evidence has indicated its involvement in tumorigenesis. However, it remains to be elucidated whether UHMK1 plays a role in the development of colorectal cancer (CRC). Here, we demonstrated that UHMK1 was frequently upregulated in CRC samples compared with adjacent normal tissue and high expression of UHMK1 predicted poor outcomes. Knockdown of UHMK1 by siRNAs restrained CRC cell proliferation and increased oxaliplatin sensitivity, whereas overexpression of UHMK1 promoted CRC cell growth and oxaliplatin resistance, suggesting that UHMK1 plays important oncogenic roles in CRC. Mechanistically, we showed that UHMK1 had a significant effect on IL6/STAT3 signaling by interacting with STAT3. The interaction of UHMK1 with STAT3 enhanced STAT3 activity in regulating gene transcription. Furthermore, we found that STAT3 could in turn transcriptionally activate UHMK1 expression in CRC cells. The complementary experiments for cell growth and oxaliplatin resistance indicated the interdependent relationship between UHMK1 and STAT3. Thus, these collective findings uncovered a new UHMK1/STAT3 positive feedback regulatory loop contributing to CRC development and chemoresistance.
UHMK1 是一种丝氨酸/苏氨酸激酶，具有 U2AF 同源基序，参与 RNA 处理和蛋白质磷酸化。越来越多的证据表明其参与了肿瘤发生。然而，UHMK1 是否在结直肠癌（CRC）的发展中发挥作用仍有待阐明。在这里，我们证明与相邻正常组织相比，CRC 样本中 UHMK1 频繁上调，高表达的 UHMK1 预示着不良预后。siRNA 敲低 UHMK1 抑制 CRC 细胞增殖并增加奥沙利铂敏感性，而 UHMK1 的过表达促进 CRC 细胞生长和奥沙利铂耐药性，表明 UHMK1 在 CRC 中发挥重要的致癌作用。从机制上讲，我们表明 UHMK1 通过与 STAT3 相互作用对 IL6/STAT3 信号有显著影响。UHMK1 与 STAT3 的相互作用增强了 STAT3 活性，从而调节基因转录。此外，我们发现 STAT3 可以在 CRC 细胞中转录激活 UHMK1 的表达。细胞生长和奥沙利铂耐药性的互补实验表明 UHMK1 和 STAT3 之间存在相互依存关系。因此，这些综合研究结果揭示了 UHMK1/STAT3 正反馈调节环在促进 CRC 发展和化疗耐药中的新作用。
