HDAC6 Regulates Radiosensitivity of Non-Small Cell Lung Cancer by Promoting Degradation of Chk1

Author:

Moses Niko,Zhang Mu,Wu Jheng-Yu,Hu Chen,Xiang Shengyan,Malysa Agnes,Jang Hyejeong,Chen Wei,Bai Wenlong,Bepler Gerold,Zhang Xiaohong MaryORCID

Abstract

ABSTRACTWe previously discovered that HDAC6 regulates the DNA damage response via modulating the homeostasis of a DNA mismatch repair protein, MSH2, through HDAC6’s ubiquitin E3 ligase activity. Here, we have reported HDAC6’s second E3 ligase substrate, a critical cell cycle checkpoint protein, Chk1. We have found that HDAC6 and Chk1 directly interact, and that HDAC6 ubiquitinates Chk1in vivo. Typical Chk1 protein levels fluctuate, peaking at G2 and subsequently resolving via the ubiquitin-proteasome pathway. However, in HDAC6 knockdown cells, Chk1 is constitutively active and fails to resolve post-ionizing radiation (IR), leading to increased radiation sensitivity. Upon IR treatment, a greater proportion of HDAC6 knockdown cells accumulated at G2/M phase when compared with control cells. Depletion or inhibition of Chk1 in HDAC6 knockdown cells renders those cells radiosensitive, suggesting that persistently high level of Chk1 could lead cells to arrest at G2/M phase and eventually, apoptosis. Clinically, we found that high levels of phosphorylated Chk1 (p-Ser317) are associated with a better overall survival in a cohort of non-small cell lung cancer (NSCLC) patients, suggesting a link between active Chk1 and lung cancer development. Overall, our results highlight a novel mechanism of Chk1 regulation at the protein level, and a possible strategy for sensitizing NSCLC to radiation via inhibiting the activity of HDAC6’s E3 ligase.

Publisher

Cold Spring Harbor Laboratory

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