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

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Abstract

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.

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Acknowledgements

This work was supported by the National key R&D program of China (2017YFC1309002), National Basic Research Program of China (973 Program, 2015CB554002), National Natural Science Foundation of China (81672821, 81472313, 81773101, 81272759, 81401927, 81302151, and 81802306), Project funded by China Postdoctoral Science Foundation (2018M633081 and 2018M633079), Natural Science Foundation of Guangdong Province (2018A030310457).

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Correspondence to Li Liang.

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