TIMELESS (Timeless Circadian Regulator)

In an orthotopic lung cancer mouse model treated with erastin (a ferroptosis inducer) and programmed cell death protein 1 (PD-1) blockade, the role of TIMELESS in therapeutic response was assessed via flow cytometry and multiplex immunofluorescence (mIF)... TIMELESS recruits CNOT3 to accelerate TF mRNA degradation, thereby suppressing ferroptosis and promoting LUAD growth. These findings suggest that the TIMELESS/TF regulatory axis may be a promising therapeutic target for LUAD.

Knocking down TIMELESS increased sensitivity to doxorubicin in thyroid cancer cells and upregulated the mRNA expression of NKX2-1 and SLC5A5. In conclusion, the overexpression of TIMELESS is associated with thyroid cancer dedifferentiation and may serve as a potential target for combination therapies.

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.

In addition, HOXC6 also regulates pathways related to chemical carcinogenesis and reactive oxygen species, with a strong association with the target gene TIMELESS, supported by binding signals in its promoter region. Here, we discuss the role of HOXC6 as a potential biomarker and therapeutic target, contributing to a deeper understanding of the HOXC6-TIMELESS axis and its implications for advancing BLCA research and therapy.

HOXC6 is upregulated in BLCA and may influence the cellular functions of BLCA by regulating the expression of the target gene TIMELESS.

Two clock genes most significantly related to survival were CRY1 and USP2. The data suggest that several clock proteins, including CRY1 and USP2, be investigated as potential therapeutic targets in MB.

In conclusion, the oscillation of circulating immune cells is profoundly altered in patients with CS, representing a convergence point of circadian rhythm disruption and metabolic and steroid hormone imbalances. Machine learning techniques proved the superiority of immune profiling over parameters such as cortisol, anthropometric and metabolic variables, and circadian gene expression analysis to identify CS activity.

This study may establish a new gastric cancer prognostic indicator based on the biological clock gene and develop new drugs for the treatment of gastric cancer using biological clock gene targets.

TIMELESS expression in LUAD tumor tissues was significantly negatively correlated with neutrophil biomarkers, dendritic cell biomarkers (HLA-DPB1, HLA-DQB1, HLA-DRA, HLA-DPA1, CD1C) and an immunophenoscore that predicted outcomes associated with the use of immune checkpoint inhibitors. These findings imply that ncRNAs-mediated TIMELESS overexpression in LUAD tumor tissues correlated with poor prognosis, reduced immune cell infiltration in the tumor microenvironment, and poor response to immune checkpoint inhibitors.

As a conclusion, HMGB1/TIM/WNT8B signal cascade was identified in this study for the first time. HMGB1 exerted its oncogenic role by activating the transcription of TIM, leading to the activation of Wnt signaling and EC progression.

TIMELESS exacerbates OSCC progression by modulating cellular proliferation and metabolic pathways, specifically by enhancing glycolysis and reducing oxidative phosphorylation, largely mediated through the SIRT1 pathway. This highlights TIMELESS as a potential target for OSCC therapeutic strategies.

This study provides new insights into the link between the circadian gene TIMELESS and the development of various malignant tumors. The findings suggest that TIMELESS could be a prospective prognostic and immunological biomarker for pan-cancer.