MYC Ran Up the Clock: The Complex Interplay between MYC and the Molecular Circadian Clock in Cancer

Abstract

The MYC oncoprotein and its family members N-MYC and L-MYC are known to drive a wide variety of human cancers. Emerging evidence suggests that MYC has a bi-directional relationship with the molecular clock in cancer. The molecular clock is responsible for circadian (~24 h) rhythms in most eukaryotic cells and organisms, as a mechanism to adapt to light/dark cycles. Disruption of human circadian rhythms, such as through shift work, may serve as a risk factor for cancer, but connections with oncogenic drivers such as MYC were previously not well understood. In this review, we examine recent evidence that MYC in cancer cells can disrupt the molecular clock; and conversely, that molecular clock disruption in cancer can deregulate and elevate MYC. Since MYC and the molecular clock control many of the same processes, we then consider competition between MYC and the molecular clock in several select aspects of tumor biology, including chromatin state, global transcriptional profile, metabolic rewiring, and immune infiltrate in the tumor. Finally, we discuss how the molecular clock can be monitored or diagnosed in human tumors, and how MYC inhibition could potentially restore molecular clock function. Further study of the relationship between the molecular clock and MYC in cancer may reveal previously unsuspected vulnerabilities which could lead to new treatment strategies.

Identification of significant molecules and signaling pathways between 2D and 3D culture methods of renal cancer cells

“…The circadian clocks and their downstream factors are responsible for a variety of physiological and pathological functions including metabolism, aging, and immunity [24][25][26][27][28][29][30][31][32][33][34] . Interestingly, Jamison B Burchett et al found that MYC in cancer cells can disturb the molecular clock, whereas the clock disruption in cancer can promote MYC 35 . Justin P Favaro et al found that the epidermal growth factor (EGF) is critical for tumor progression in renal cancers, which can be considered as a potential drug target 36 .…”

Role of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment Resistance

“…This may be related to the overexpressed stemness transcription factors speeding the cell cycle and forcing adaptation of its checkpoints, as discussed in Section 4 and illustrated in Figure 2 . In addition, the direct competition of the main reprogramming transcription factor, MYC/MAX, with the CLOCK/BMAL1 dimer [ 125 ] in the G1/S and G2M checkpoints [ 135 ], which can be overcome through upregulated MYC [ 136 ] (as designated on Figure 2 ), should be highlighted.…”

Role of the circadian clock “Death-Loop” in the DNA damage response underpinning cancer treatment resistance

“…This may be related to the overexpressed ESC transcription factors speeding the cell cycle and forcing adaptation of its checkpoints as discussed in section 4 and illustrated in Fig.2. In addition, the direct competition of the main reprogramming transcription factor, MYC/MAX, with the CLOCK/BMAL1 dimer [80] in the G1/S and G2M checkpoints [89], which can be overcome through upregulated MYC [90](as designated on Fig.2), should be highlighted.…”

“…2. In addition, the direct competition of the main reprogramming transcription factor, MYC/MAX, with the CLOCK/BMAL1 dimer [79] in the G1/S and G2M checkpoints [89], which can be overcome through upregulated MYC [90](as designated on Fig. 2), should be highlighted.…”