A new KSRP-binding compound suppresses distant metastasis of colorectal cancer by targeting the oncogenic KITENIN complex

Eun Ae Kim,Keon Young Kim,Jeong A Bae,Hyung-Ho Ha,Yoo-Seung Ko,Hangun Kim,Ik Joo Chung,Woo Kyun Bae,Young Hyun Yu,Sung Jin Kim,So-Yeon Park,Kyung Keun Kim

doi:10.1186/s12943-021-01368-w

Abstract

BackgroundDistant metastasis is the major cause of death in patients with colorectal cancer (CRC). Previously, we identified KITENIN as a metastasis-enhancing gene and suggested that the oncogenic KITENIN complex is involved in metastatic dissemination of KITENIN-overexpressing CRC cells. Here, we attempted to find substances targeting the KITENIN complex and test their ability to suppress distant metastasis of CRC.MethodsWe screened a small-molecule compound library to find candidate substances suppressing the KITENIN complex in CRC cells. We selected a candidate compound and examined its effects on the KITENIN complex and distant metastasis through in vitro assays, a molecular docking model, and in vivo tumor models.ResultsAmong several compounds, we identified DKC1125 (Disintegrator of KITENIN Complex #1125) as the best candidate. DKC1125 specifically suppressed KITENIN gain of function. After binding KH-type splicing regulatory protein (KSRP), DKC1125 degraded KITENIN and Dvl2 by recruiting RACK1 and miRNA-124, leading to the disintegration of the functional KITENIN–KSRP–RACK1–Dvl2 complex. A computer docking model suggested that DKC1125 specifically interacted with the binding pocket of the fourth KH-domain of KSRP. KITENIN-overexpressing CRC cells deregulated certain microRNAs and were resistant to 5-fluorouracil, oxaliplatin, and cetuximab. DKC1125 restored sensitivity to these drugs by normalizing expression of the deregulated microRNAs, including miRNA-124. DKC1125 effectively suppressed colorectal liver metastasis in a mouse model. Interestingly, the combination of DKC1125 with 5-fluorouracil suppressed metastasis more effectively than either drug alone.ConclusionDKC1125 targets the KITENIN complex and could therefore be used as a novel therapeutic to suppress liver metastasis in CRC expressing high levels of KITENIN.

Highlights

Distant metastasis is the major cause of death in patients with colorectal cancer (CRC)
Compound Disintegrator of KITENIN Complex #1125 (DKC1125) blocks AP-1 activity and cell invasiveness in KAI1 C-terminal interacting tetraspanin (KITENIN)-overexpressing cells We previously reported that overexpressing KITENIN promotes activation of AP-1 through interaction with
To investigate how DKC1125 affects the function of KITENIN after binding KH-type splicing regulatory protein (KSRP), we examined the effect of DKC1125 on the level of c-Jun, a downstream effector of the KITENIN axis that is involved in cell invasion [10]

Summary

Introduction

Distant metastasis is the major cause of death in patients with colorectal cancer (CRC). We identified KITENIN as a metastasis-enhancing gene and suggested that the oncogenic KITENIN complex is involved in metastatic dissemination of KITENIN-overexpressing CRC cells. We attempted to find substances targeting the KITENIN complex and test their ability to suppress distant metastasis of CRC. The overall survival of patients with colorectal cancer (CRC) has increased due to advances in chemotherapy and molecular targeted therapy [1, 2]. CT-26 mouse colon cancer cells overexpressing KITE NIN exhibit increased invasiveness and tumorigenicity and early hepatic metastasis resulting from KITENIN gain of function (KITENIN-GOF) [6], but these effects are suppressed by KITENIN siRNA [7,8,9].

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