TIMELESS deficiency sensitizes thyroid cancer to cisplatin treatment via the DNA damage repair pathway

The circadian rhythm plays a crucial role in thyroid cancer progression. DNA damage repair (DDR) pathways are closely associated with the sensitivity to cisplatin. However, the role of circadian rhythm genes on cisplatin resistance in thyroid cancer remains undefined.

Panels of molecular screening were achieved by signaling antibody array. Molecular expressions were established via western blotting and polymerase chain reaction (PCR). Multiple assays (Cell Counting Kit-8, colony formation, Transwell) were used to assess cellular dynamics. The xenograft tumor model was employed for in vivo therapeutic evaluation.

BCPAP and KTC-1 cells were more resistant to cisplatin than other thyroid cancer cell lines, and DDR pathway activation was detected upon cisplatin treatment in BCPAP and KTC-1. The target that affects cisplatin efficacy was screened among circadian rhythm genes, and found that TIMELESS expression was correlated with the sensitivity to cisplatin and malignant signatures of thyroid cancer. TIMELESS knockdown impaired the DDR pathway activation, and significantly enhanced the efficacy of cisplatin treatment in vitro and in vivo.

The newly identified signaling involving circadian rhythm genes and DDR pathways provided mechanistic insights into the cisplatin sensitization strategy in thyroid cancer. Therefore, TIMELESS may be a promising target in thyroid cancer therapeutics.