DAPK2 activates NF-κB through autophagy-dependent degradation of I-κBα during thyroid cancer development and progression.

Background: Death-associated protein kinase 2 (DAPK2) is a serine/threonine kinase, which has been implicated in autophagy and apoptosis. DAPK2 functions as a tumor suppressor in various cancers. However, the role of DAPK2 in thyroid cancer (TC) is unclear.

Methods: RNA sequencing of human TC samples was performed to identify differentially expressed genes that may play a role in TC development. The messenger RNA (mRNA) expression of DAPK2 was verified by quantitative real-time polymerase chain reaction (qRT-PCR). To investigate the role of DAPK2 in TC development, DAPK2 was knocked down and overexpressed in a TTA1 cell line. The effect of DAPK2 on cell proliferation, sensitization of TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis and tumor growth was examined. The effect of DAPK2 on autophagy and NF-κB activation was investigated to address the underlying mechanism.

Results: DAPK2 was upregulated in TC. Knockdown of DAPK2 in TTA1 cells led to reduced cell proliferation, sensitization of TRAIL-induced apoptosis, and restricted tumor growth both and , while overexpression of DAPK2 exhibited the opposite effect. Mechanistically, DAPK2 promoted autophagy as demonstrated by the accumulation of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II, which correlated with the level of nuclear factor-κB (NF-κB) activation. Knockdown of inhibitory-κBα (I-κBα) in short hairpin (sh) DAPK2 TTA1 cells restored the activity of NF-κB, suggesting DAPK2 activated NF-κB through autophagy-mediated I-κBα degradation.

Conclusions: Our findings revealed a pivotal role of DAPK2 in thyroid carcinogenesis, being required for tumor growth and for resistance to TRAIL-induced apoptosis through autophagy-mediated I-κBα degradation. This result provides a novel target for the therapy of TC.