Conflicting pro- and anti-tumoral reports of the clock transcription factor BHLHE41 involvement in oncogenesis at the advent of spatiotemporal multiomics

The bHLH-Orange transcriptional repressor BHLHE41 is considered a member of the fifth clock gene family. Diverse mechanisms of gene expression regulation and interaction with numerous transcription factors, epigenetic modifiers and master regulators often in feedback loops characterize BHLHE41 activity. BHLHE41 may be involved in oncogenesis by various mechanisms due to its pleiotropic functions. Responsive to various signals such as hypoxia or chemotherapeutics, BHLHE1 controls cell fate as a regulator of proliferation, differentiation, DNA damage repair and apoptosis. Conflicting reports of pro- and anti-tumoral effects suggest context-dependent and tumor-specific effects. BHLHE1 involvement in key mechanisms repeatedly reported include the hypoxia response and the inhibition of apoptosis and epithelial-mesenchymal transition. The sensitive balance between BHLHE41 and its paralog BHLHE40, characterized by shared and non-redundant complementary or opposing moonlighting functions, may be critical in oncogenesis. Addressing the functional complexity and heterogeneity as well as the short and long term dynamics of BHLHE41 biology by emerging spatial and temporal omics technologies may be of practical importance for precision oncology and personalized care, drug development and selection, early diagnosis and patient monitoring, or chrono-chemotherapy.