Kinome-wide siRNA screen identifies a DCLK2-TBK1 oncogenic signaling axis in clear cell renal cell carcinoma

Lianxin Hu; Yanfeng Zhang; Lei Guo; Hua Zhong; Ling Xie; Jin Zhou; Chengheng Liao; Hongwei Yao; Jun Fang; Hongyi Liu; Cheng Zhang; Hui Zhang; Xiaoqiang Zhu; Maowu Luo; Alex von Kriegsheim; Bufan Li; Weibo Luo; Xuewu Zhang; Xian Chen; Joshua T. Mendell; Lin Xu; Payal Kapur; Albert S. Baldwin; James Brugarolas; Qing Zhang

doi:10.1016/j.molcel.2023.12.010

Kinome-wide siRNA screen identifies a DCLK2-TBK1 oncogenic signaling axis in clear cell renal cell carcinoma

Lianxin Hu, Yanfeng Zhang, Lei Guo, Hua Zhong, Ling Xie, Jin Zhou, Chengheng Liao, Hongwei Yao, Jun Fang, Hongyi Liu, Cheng Zhang, Hui Zhang, Xiaoqiang Zhu, Maowu Luo, Alex von Kriegsheim, Bufan Li, Weibo Luo, Xuewu Zhang, Xian Chen, Joshua T. MendellLin Xu, Payal Kapur, Albert S. Baldwin, James Brugarolas, Qing Zhang

Research output: Contribution to journal › Article › peer-review

Abstract

TANK-binding kinase 1 (TBK1) is a potential therapeutic target in multiple cancers, including clear cell renal cell carcinoma (ccRCC). However, targeting TBK1 in clinical practice is challenging. One approach to overcome this challenge would be to identify an upstream TBK1 regulator that could be targeted therapeutically in cancer specifically. In this study, we perform a kinome-wide small interfering RNA (siRNA) screen and identify doublecortin-like kinase 2 (DCLK2) as a TBK1 regulator in ccRCC. DCLK2 binds to and directly phosphorylates TBK1 on Ser172. Depletion of DCLK2 inhibits anchorage-independent colony growth and kidney tumorigenesis in orthotopic xenograft models. Conversely, overexpression of DCLK2²⁰³, a short isoform that predominates in ccRCC, promotes ccRCC cell growth and tumorigenesis in vivo. Mechanistically, DCLK2²⁰³ elicits its oncogenic signaling via TBK1 phosphorylation and activation. Taken together, these results suggest that DCLK2 is a TBK1 activator and potential therapeutic target for ccRCC.

Original language	English (US)
Pages (from-to)	776-790.e5
Journal	Molecular cell
Volume	84
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2023.12.010
State	Published - Feb 15 2024

Keywords

DCLK2
NMD pathway
TBK1
ccRCC
oncogene

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2023.12.010

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Hu, L., Zhang, Y., Guo, L., Zhong, H., Xie, L., Zhou, J., Liao, C., Yao, H., Fang, J., Liu, H., Zhang, C., Zhang, H., Zhu, X., Luo, M., von Kriegsheim, A., Li, B., Luo, W., Zhang, X., Chen, X., ... Zhang, Q. (2024). Kinome-wide siRNA screen identifies a DCLK2-TBK1 oncogenic signaling axis in clear cell renal cell carcinoma. Molecular cell, 84(4), 776-790.e5. https://doi.org/10.1016/j.molcel.2023.12.010

Hu, L, Zhang, Y, Guo, L, Zhong, H, Xie, L, Zhou, J, Liao, C, Yao, H, Fang, J, Liu, H, Zhang, C, Zhang, H, Zhu, X, Luo, M, von Kriegsheim, A, Li, B, Luo, W, Zhang, X, Chen, X, Mendell, JT , Xu, L , Kapur, P, Baldwin, AS, Brugarolas, J & Zhang, Q 2024, 'Kinome-wide siRNA screen identifies a DCLK2-TBK1 oncogenic signaling axis in clear cell renal cell carcinoma', Molecular cell, vol. 84, no. 4, pp. 776-790.e5. https://doi.org/10.1016/j.molcel.2023.12.010

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title = "Kinome-wide siRNA screen identifies a DCLK2-TBK1 oncogenic signaling axis in clear cell renal cell carcinoma",

abstract = "TANK-binding kinase 1 (TBK1) is a potential therapeutic target in multiple cancers, including clear cell renal cell carcinoma (ccRCC). However, targeting TBK1 in clinical practice is challenging. One approach to overcome this challenge would be to identify an upstream TBK1 regulator that could be targeted therapeutically in cancer specifically. In this study, we perform a kinome-wide small interfering RNA (siRNA) screen and identify doublecortin-like kinase 2 (DCLK2) as a TBK1 regulator in ccRCC. DCLK2 binds to and directly phosphorylates TBK1 on Ser172. Depletion of DCLK2 inhibits anchorage-independent colony growth and kidney tumorigenesis in orthotopic xenograft models. Conversely, overexpression of DCLK2203, a short isoform that predominates in ccRCC, promotes ccRCC cell growth and tumorigenesis in vivo. Mechanistically, DCLK2203 elicits its oncogenic signaling via TBK1 phosphorylation and activation. Taken together, these results suggest that DCLK2 is a TBK1 activator and potential therapeutic target for ccRCC.",

keywords = "DCLK2, NMD pathway, TBK1, ccRCC, oncogene",

author = "Lianxin Hu and Yanfeng Zhang and Lei Guo and Hua Zhong and Ling Xie and Jin Zhou and Chengheng Liao and Hongwei Yao and Jun Fang and Hongyi Liu and Cheng Zhang and Hui Zhang and Xiaoqiang Zhu and Maowu Luo and {von Kriegsheim}, Alex and Bufan Li and Weibo Luo and Xuewu Zhang and Xian Chen and Mendell, {Joshua T.} and Lin Xu and Payal Kapur and Baldwin, {Albert S.} and James Brugarolas and Qing Zhang",

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doi = "10.1016/j.molcel.2023.12.010",

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T1 - Kinome-wide siRNA screen identifies a DCLK2-TBK1 oncogenic signaling axis in clear cell renal cell carcinoma

AU - Hu, Lianxin

AU - Zhang, Yanfeng

AU - Guo, Lei

AU - Zhong, Hua

AU - Xie, Ling

AU - Zhou, Jin

AU - Liao, Chengheng

AU - Yao, Hongwei

AU - Fang, Jun

AU - Liu, Hongyi

AU - Zhang, Cheng

AU - Zhang, Hui

AU - Zhu, Xiaoqiang

AU - Luo, Maowu

AU - von Kriegsheim, Alex

AU - Li, Bufan

AU - Luo, Weibo

AU - Zhang, Xuewu

AU - Chen, Xian

AU - Mendell, Joshua T.

AU - Xu, Lin

AU - Kapur, Payal

AU - Baldwin, Albert S.

AU - Brugarolas, James

AU - Zhang, Qing

PY - 2024/2/15

Y1 - 2024/2/15

N2 - TANK-binding kinase 1 (TBK1) is a potential therapeutic target in multiple cancers, including clear cell renal cell carcinoma (ccRCC). However, targeting TBK1 in clinical practice is challenging. One approach to overcome this challenge would be to identify an upstream TBK1 regulator that could be targeted therapeutically in cancer specifically. In this study, we perform a kinome-wide small interfering RNA (siRNA) screen and identify doublecortin-like kinase 2 (DCLK2) as a TBK1 regulator in ccRCC. DCLK2 binds to and directly phosphorylates TBK1 on Ser172. Depletion of DCLK2 inhibits anchorage-independent colony growth and kidney tumorigenesis in orthotopic xenograft models. Conversely, overexpression of DCLK2203, a short isoform that predominates in ccRCC, promotes ccRCC cell growth and tumorigenesis in vivo. Mechanistically, DCLK2203 elicits its oncogenic signaling via TBK1 phosphorylation and activation. Taken together, these results suggest that DCLK2 is a TBK1 activator and potential therapeutic target for ccRCC.

AB - TANK-binding kinase 1 (TBK1) is a potential therapeutic target in multiple cancers, including clear cell renal cell carcinoma (ccRCC). However, targeting TBK1 in clinical practice is challenging. One approach to overcome this challenge would be to identify an upstream TBK1 regulator that could be targeted therapeutically in cancer specifically. In this study, we perform a kinome-wide small interfering RNA (siRNA) screen and identify doublecortin-like kinase 2 (DCLK2) as a TBK1 regulator in ccRCC. DCLK2 binds to and directly phosphorylates TBK1 on Ser172. Depletion of DCLK2 inhibits anchorage-independent colony growth and kidney tumorigenesis in orthotopic xenograft models. Conversely, overexpression of DCLK2203, a short isoform that predominates in ccRCC, promotes ccRCC cell growth and tumorigenesis in vivo. Mechanistically, DCLK2203 elicits its oncogenic signaling via TBK1 phosphorylation and activation. Taken together, these results suggest that DCLK2 is a TBK1 activator and potential therapeutic target for ccRCC.

KW - DCLK2

KW - NMD pathway

KW - TBK1

KW - ccRCC

KW - oncogene

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JF - Molecular cell

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ER -

Kinome-wide siRNA screen identifies a DCLK2-TBK1 oncogenic signaling axis in clear cell renal cell carcinoma

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