CDK5 Activates Hippo Signaling to Confer Resistance to Radiation Therapy Via Upregulating TAZ in Lung Cancer.

Abstract

PURPOSE:

Tumor resistance to radiation therapy is a therapeutic challenge in the treatment of patients with non-small cell lung cancer. Cyclin-dependent kinase 5 (CDK5) has been proposed to participate in cell proliferation, migration and invasion, drug resistance, and immune evasion. However, the functions and regulatory mechanisms of CDK5 in lung cancer radioresistance have not been investigated.

METHODS AND MATERIALS:

DNA damage response and repair were measured by neutral comet assay and γ-H2AX and Rad51 foci staining. The biological functions of CDK5 in lung cancer radioresistance were investigated with clonogenic survival assays and xenograft tumor models. Small interfering RNAs and short hairpin RNAs were used to knock down CDK5 in A549 and H1299 cells. The effects of CDK5 depletion on the tumorigenic behaviors of lung cancer cells were evaluated in vitro and in vivo. Gene expression was examined by RNA-seq and quantitative real-time polymerase chain reaction.

RESULTS:

We report that CDK5 depletion impairs lung cancer progression and radioresistance in vitro and in vivo. Mechanistically, we identify TAZ, a component of the Hippo pathway, as a critical downstream effector of CDK5. Loss of CDK5 downregulates TAZ expression and attenuates Hippo signaling activation. Importantly, we provide evidence that TAZ is the major effector mediating the biological functions of CDK5 in lung cancer.

CONCLUSIONS:

These results illustrate that CDK5 activates Hippo signaling via TAZ to participate in tumorigenesis and radioresistance, suggesting that CDK5 may be a promising radiosensitization target for the treatment of lung cancer.

• Authors: Yulan Zeng, Quan Liu, Ye Wang, Chen Tian, Qifan Yang, Ye Zhao, Li Liu, Gang Wu, Shuangbing Xu
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 108 Issue 3 Pg. 758-769 (11 01 2020) ISSN: 1879-355X [Electronic] United States
• PMID: 32407930 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• H2AX protein, human
• Histones
• Neoplasm Proteins
• RNA, Small Interfering
• Transcription Factors
• Acyltransferases
• TAFAZZIN protein, human
• Cyclin-Dependent Kinase 5
• Protein Serine-Threonine Kinases
• CDK5 protein, human
• RAD51 protein, human
• Rad51 Recombinase

Topics

• A549 Cells
• Acyltransferases
• Animals
• Cell Line, Tumor
• Comet Assay
• Cyclin-Dependent Kinase 5 (deficiency, genetics, metabolism)
• DNA Damage
• DNA Repair
• Disease Progression
• Down-Regulation
• Fluorescent Antibody Technique
• Gene Knockdown Techniques
• Gene Silencing
• Heterografts
• Hippo Signaling Pathway
• Histones (analysis)
• Humans
• Lung Neoplasms (chemistry, genetics, metabolism, radiotherapy)
• Mice
• Neoplasm Proteins (deficiency, genetics, metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• RNA, Small Interfering
• Rad51 Recombinase (analysis)
• Radiation Tolerance (physiology)
• Transcription Factors (metabolism)
• Up-Regulation