KNK437 restricts the growth and metastasis of colorectal cancer via targeting DNAJA1/CDC45 axis

• Published in: Oncogene Vol. 39; no. 2; pp. 249 - 261
• Main Authors: Yang, Shaoshan, Ren, Xiaoli, Liang, Yunshi, Yan, Yongrong, Zhou, Yangshu, Hu, Jinlong, Wang, Zhizhi, Song, Fuyao, Wang, Feifei, Liao, Wangjun, Liao, Wenting, Ding, Yanqing, Liang, Li
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09-01-2020; Nature Publishing Group
• Subjects: 13/1; 13/109; 13/2; 13/51; 38/44; 38/77; 38/89; 631/67/1059/602; 631/67/1504/1885; 64/60; 82/80; Animals; Apoptosis; Benzhydryl Compounds - pharmacology; Cdc45 protein; Cell Biology; Cell cycle; Cell Cycle Proteins - genetics; Cell division; Cell proliferation; Cell Proliferation - drug effects; Chemotherapy; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Cycle protein; E2F1 protein; E2F1 Transcription Factor - genetics; Female; Gene Expression Regulation, Neoplastic - drug effects; Growth; Health aspects; Heat shock proteins; Heat-Shock Proteins - antagonists & inhibitors; Hsp27 protein; HSP40 Heat-Shock Proteins - genetics; Hsp40 protein; Hsp70 protein; Hsp90 protein; Human Genetics; Humans; Internal Medicine; Lymph nodes; Male; Medical research; Medicine; Medicine & Public Health; Medicine, Experimental; Metastases; Metastasis; Mice; Neoplasm Metastasis; Oncology; Proteins; Pyrrolidinones - pharmacology; Signal Transduction - drug effects; Xenograft Model Antitumor Assays; China
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-019-0978-0

As an inhibitor of heat shock proteins (HSPs), KNK437 has been reported to play an anti-tumor role in several cancers. But its therapeutic effect and mechanisms in colorectal cancer (CRC) remain unclear. Here, KNK437 sharply inhibited the level of DnaJ heat shock protein family (Hsp40) member A1 (DNAJA1), followed by DNAJB1, but had little effect on the levels of HSP27, HSP105, HSP90, and HSP70 in CRC cells. DNAJA1 promoted CRC cell proliferation in vitro and tumor growth and metastasis in vivo. Mechanistically, DNAJA1 was activated by E2F transcription factor 1 (E2F1) and then promoted cell cycle by stabilizing cell division cycle protein 45 (CDC45), which could be reversed by KNK437. DNAJA1 was significantly upregulated in CRC tissues and positively correlated with serosa invasion, lymph node metastasis. High level of DNAJA1 predicted poor prognosis for CRC patients. Its expression was highly linked with E2F1 and CDC45 in CRC tissues. More importantly, KNK437 significantly suppressed the growth of DNAJA1 expressing tumor in vivo. The combined treatment of KNK437 with 5-FU/L-OHP chemotherapy reduced liver metastasis of CRC. These data reveal a novel mechanism of KNK437 in anti-tumor therapy of CRC and provides a newly therapeutic strategy with potential translation to the CRC patients.