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

Mol Cell. 2024 Feb 15;84(4):776-790.e5. doi: 10.1016/j.molcel.2023.12.010. Epub 2024 Jan 10.

Authors

Lianxin Hu¹, Yanfeng Zhang², Lei Guo², Hua Zhong³, Ling Xie⁴, Jin Zhou¹, Chengheng Liao¹, Hongwei Yao¹, Jun Fang¹, Hongyi Liu¹, Cheng Zhang¹, Hui Zhang⁵, Xiaoqiang Zhu⁶, Maowu Luo¹, Alex von Kriegsheim⁷, Bufan Li⁸, Weibo Luo⁹, Xuewu Zhang¹⁰, Xian Chen⁴, Joshua T Mendell¹¹, Lin Xu², Payal Kapur¹², Albert S Baldwin¹³, James Brugarolas¹⁴, Qing Zhang¹⁵

Affiliations

¹ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
² Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
³ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁴ Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
⁵ Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁶ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁷ Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
⁸ Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁹ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
¹⁰ Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
¹¹ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
¹² Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
¹³ Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
¹⁴ Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
¹⁵ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: qing.zhang@utsouthwestern.edu.

PMID: 38211588
PMCID: PMC10922811 (available on 2025-02-15)
DOI: 10.1016/j.molcel.2023.12.010

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.

MeSH terms

Carcinogenesis / genetics
Carcinoma, Renal Cell* / metabolism
Cell Line, Tumor
Cell Proliferation / genetics
Cell Transformation, Neoplastic / genetics
Doublecortin-Like Kinases
Gene Expression Regulation, Neoplastic
Humans
Kidney Neoplasms* / metabolism
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism

Substances

Doublecortin-Like Kinases
Protein Serine-Threonine Kinases
RNA, Small Interfering
TBK1 protein, human
DCLK2 protein, human

Abstract

MeSH terms

Substances

Grants and funding