Skip to main content
Have a personal or library account? Click to login
Conflicting pro- and anti-tumoral reports of the clock transcription factor BHLHE41 involvement in oncogenesis at the advent of spatiotemporal multiomics Cover

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

By:   
Open Access
|Jul 2026

References

  1. Honma S, Kawamoto T, Takagi Y, et al. Dec1 and Dec2 are regulators of the mammalian molecular clock. Nature. 2002;419(6909):841-4.
  2. Kato Y, Kawamoto T, Fujimoto K, Noshiro M. DEC1/STRA13/SHARP2 and DEC2/SHARP1 coordinate physiological processes, including circadian rhythms in response to environmental stimuli. Curr Top Dev Biol. 2014;110:339-72.
  3. Ow JR, Tan YH, Jin Y, Bahirvani AG, Taneja R. Stra13 and Sharp-1, the non-grouchy regulators of development and disease. Curr Top Dev Biol. 2014;110:317-38.
  4. Kurien PA, Chong SY, Ptáček LJ, Fu YH. Sick and tired: how molecular regulators of human sleep schedules and duration impact immune function. Curr Opin Neurobiol. 2013;23(5):873-9.
  5. UniProt [cited 2025 October 20]. Available from: http://www.uniprot.org.
  6. Sun H, Ghaffari S, Taneja R. bHLH-Orange Transcription Factors in Development and Cancer. Transl Oncogenomics. 2007;2:107-20.
  7. Cho Y, Noshiro M, Choi M, et al. The basic helix-loop-helix proteins differentiated embryo chondrocyte (DEC) 1 and DEC2 function as corepressors of retinoid X receptors. Mol Pharmacol. 2009;76(6):1360-9.
  8. Fujimoto K, Shen M, Noshiro M, et al. Molecular cloning and characterization of DEC2, a new member of basic helix-loop-helix proteins. Biochem Biophys Res Commun. 2001;280(1):164-71.
  9. Fujimoto K, Hamaguchi H, Hashiba T, et al. Transcriptional repression by the basic helix-loop-helix protein Dec2: multiple mechanisms through E-box elements. Int J Mol Med. 2007;19(6):925-32.
  10. Kondo J, Sato F, Fujimoto K, et al. 57Arg in the bHLH transcription factor DEC2 is essential for the suppression of CLOCK/BMAL2-mediated transactivation. Int J Mol Med. 2006;17(6):1053-6.
  11. Liu B, Wang T, Mei W, et al. Small ubiquitin-like modifier (SUMO) protein-specific protease 1 de-SUMOylates Sharp-1 protein and controls adipocyte Differentiation. J Biol Chem 2014;289(32):22358-64
  12. Wang Y, Shankar SR, Kher D, Ling BM, Taneja R. Sumoylation of the basic helix-loop-helix transcription factor sharp-1 regulates recruitment of the histone methyltransferase G9a and function in myogenesis. J Biol Chem. 2013;288(24):17654-62.
  13. Rossner MJ, Dörr J, Gass P, Schwab MH, Nave KA. SHARPs: mammalian enhancer-of-split- and hairy-related proteins coupled to neuronal stimulation. Mol Cell Neurosci. 1997;10(3-4):460-75.
  14. Azmi S, Taneja R. Embryonic expression of mSharp-1/mDEC2, which encodes a basic helix-loop-helix transcription factor. Mech Dev. 2002;114(1-2):181-5.
  15. Chen L, Zhou J, Xu H, Xu G, Xue J. Identification and developmental expression of Dec2 in zebrafish. Fish Physiol Biochem. 2010;36(3):667-675.
  16. Guillaumond F, Lacoche S, Dulong S, et al. Altered Stra13 and Dec2 circadian gene expression in hypoxic cells. Biochem Biophys Res Commun. 2008;369(4):1184-9.
  17. Ueda HR, Hayashi S, Chen W, et al. System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat Genet. 2005;37(2):187-92.
  18. Li Y, Xie M, Song X, Gragen S, Sachdeva K, Wan Y, Yan B. DEC1 negatively regulates the expression of DEC2 through binding to the E-box in the proximal promoter. J Biol Chem. 2003;278(19):16899-907.
  19. Hamaguchi H, Fujimoto K, Kawamoto T, et al. Expression of the gene for Dec2, a basic helix-loop-helix transcription factor, is regulated by a molecular clock system. Biochem J. 2004;382(Pt 1):43-50.
  20. Ozaki N, Noshiro M, Kawamoto T, et al. Regulation of basic helix-loop-helix transcription factors Dec1 and Dec2 by RORα and their roles in adipogenesis. Genes Cells. 2012;17(2):109-21.
  21. Inaguma S, Riku M, Hashimoto M, Murakami H, Saga S, Ikeda H, Kasai K. GLI1 interferes with the DNA mismatch repair system in pancreatic cancer through BHLHE41-mediated suppression of MLH1. Cancer Res. 2013;73(24):7313-23.
  22. Yang XO, Angkasekwinai P, Zhu J, et al. Requirement for the basic helix-loop-helix transcription factor Dec2 in initial TH2 lineage commitment. Nat Immunol. 2009;10(12):1260-6.
  23. Miyazaki K, Kawamoto T, Tanimoto K, Nishiyama M, Honda H, Kato Y. Identification of functional hypoxia response elements in the promoter region of the DEC1 and DEC2 genes. J Biol Chem. 2002;277(49):47014-21.
  24. Montagner M, Enzo E, Forcato M, et al. SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors. Nature. 2012;487(7407):380-4.
  25. Azmi S, Sun H, Ozog A, Taneja R. mSharp-1/DEC2, a basic helix-loop-helix protein functions as a transcriptional repressor of E box activity and Stra13 expression. J Biol Chem. 2003;278(22):20098-109.
  26. Azmi S, Ozog A, Taneja R. Sharp-1/DEC2 inhibits skeletal muscle differentiation through repression of myogenic transcription factors. J Biol Chem. 2004;279(50):52643-52.
  27. Cho Y, Noshiro M, Choi M, et al. The basic helix-loop-helix proteins differentiated embryo chondrocyte (DEC) 1 and DEC2 function as corepressors of retinoid X receptors. Mol Pharmacol. 2009;76(6):1360-9.
  28. Choi SM, Cho HJ, Cho H, Kim KH, Kim JB, Park H. Stra13/DEC1 and DEC2 inhibit sterol regulatory element binding protein-1c in a hypoxia-inducible factor-dependent mechanism. Nucleic Acids Res. 2008;36(20):6372-85.
  29. Gulbagci NT, Li L, Ling B, et al. SHARP1/DEC2 inhibits adipogenic differentiation by regulating the activity of C/EBP. EMBO Rep. 2009;10(1):79-86.
  30. Bret C, Desmots-Loyer F, Moreaux J, Fest T. BHLHE41, a transcriptional repressor involved in physiological processes and tumor development. Cell Oncol (Dordr). 2025;48(1):43-66.
  31. Sato F, Bhawal UK, Yoshimura T, Muragaki Y. DEC1 and DEC2 Crosstalk between Circadian Rhythm and Tumor Progression. J Cancer. 2016;7(2):153-9.
  32. Furukawa T, Mimami K, Nagata T, Yamamoto M, Sato M, Tanimoto A. Approach to Functions of BHLHE41/DEC2 in Non-Small Lung Cancer Development. Int J Mol Sci. 2023;24(14):11731.
  33. Fang W, Li Q, Wang M, Zheng M, Xu H. DEC2 Serves as Potential Tumor Suppressor in Breast Carcinoma. Dis Markers. 2020;2020:6053154.
  34. Piccolo S, Enzo E, Montagner M. p63, Sharp1, and HIFs: master regulators of metastasis in triple-negative breast cancer. Cancer Res. 2013;73(16):4978-81.
  35. Wu Y, Sato H, Suzuki T, et al. Involvement of c-Myc in the proliferation of MCF-7 human breast cancer cells induced by bHLH transcription factor DEC2. Int J Mol Med. 2015;35(3):815-20.
  36. Liu Y, Sato F, Kawamoto T, et al. Anti-apoptotic effect of the basic helix-loop-helix (bHLH) transcription factor DEC2 in human breast cancer cells. Genes Cells. 2010;15(4):315-25.
  37. Wu Y, Sato F, Bhawal UK, et al. Basic helix-loop-helix transcription factors DEC1 and DEC2 regulate the paclitaxel-induced apoptotic pathway of MCF-7 human breast cancer cells. Int J Mol Med. 2011;27(4):491-5.
  38. Li Y, Shen Q, Kim HT, et al. The rexinoid bexarotene represses cyclin D1 transcription by inducing the DEC2 transcriptional repressor. Breast Cancer Res Treat. 2011;128(3):667-77.
  39. Nagasawa S, Ikeda K, Horie-Inoue K, et al. Systematic Identification of Characteristic Genes of Ovarian Clear Cell Carcinoma Compared with High-Grade Serous Carcinoma Based on RNA-Sequencing. Int J Mol Sci. 2019;20(18):4330..
  40. Yunokawa M, Tanimoto K, Nakamura H, et al. Differential regulation of DEC2 among hypoxia-inducible genes in endometrial carcinomas. Oncol Rep. 2007;17(4):871-8.
  41. Liao Y, He X, Qiu H, C et al. Suppression of the epithelial-mesenchymal transition by SHARP1 is linked to the NOTCH1 signaling pathway in metastasis of endometrial cancer. BMC Cancer. 2014;14:487.
  42. Asanoma K, Liu G, Yamane T, et al. Regulation of the Mechanism of TWIST1 Transcription by BHLHE40 and BHLHE41 in Cancer Cells. Mol Cell Biol. 2015;35(24):4096-109.
  43. Liu Q, Wu Y, Yoshizawa T, et al. Basic helix-loop-helix transcription factor DEC2 functions as an anti-apoptotic factor during paclitaxel-induced apoptosis in human prostate cancer cells. Int J Mol Med. 2016;38(6):1727-1733.
  44. Liu Q, Wu Y, Seino H, et al. Correlation between DEC1/DEC2 and epithelialmesenchymal transition in human prostate cancer PC3 cells. Mol Med Rep. 2018;18(4):3859-3865.
  45. Tuerxun M, Zheng X, Xu J, Yang Q, Yuan T, Zhang C, Zhou S. High expression of DEC2 distinguishes chondroblastic osteosarcoma and promotes tumour growth by activating the VEGFC/VEGFR2 signalling pathway. J Cell Mol Med. 2024;28(11):e18462.
  46. Hu T, He N, Yang Y, Yin C, Sang N, Yang Q. DEC2 expression is positively correlated with HIF-1 activation and the invasiveness of human osteosarcomas. J Exp Clin Cancer Res. 2015;34(1):22.
  47. Jiang B, Mu W, Wang J, et al. MicroRNA-138 functions as a tumor suppressor in osteosarcoma by targeting differentiated embryonic chondrocyte gene 2. J Exp Clin Cancer Res. 2016;35:69.
  48. Wu H, Yu Z, Chen Q, Li D, Chen W. MicroRNA-301a inhibits the progression of osteosarcoma by regulating DEC2. J BUON. 2020;25(2):1013-1021.
  49. Grampp S, Schmid V, Salama R, et al. Multiple renal cancer susceptibility polymorphisms modulate the HIF pathway. PLoS Genet. 2017;13(7):e1006872.
  50. Shen Z, Zhu L, Zhang C, Cui X, Lu J. Overexpression of BHLHE41, correlated with DNA hypomethylation in 3’UTR region, promotes the growth of human clear cell renal cell carcinoma. Oncol Rep. 2019;41(4):2137-2147. .
  51. Bigot P, Colli LM, Machiela MJ, et al. Functional characterization of the 12p12.1 renal cancer-susceptibility locus implicates BHLHE41. Nat Commun. 2016;7:12098.
  52. Yang X, Wu JS, Li M, et al. Inhibition of DEC2 is necessary for exiting cell dormancy in salivary adenoid cystic carcinoma. J Exp Clin Cancer Res. 2021;40(1):169.
  53. Wu Y, Sato F, Bhawal UK, et al. BHLH transcription factor DEC2 regulates pro-apoptotic factor Bim in human oral cancer HSC-3 cells. Biomed Res. 2011;33:75–82.
  54. Sato H, Wu Y, Kato Y, et al. DEC2 expression antagonizes cisplatininduced apoptosis in human esophageal squamous cell carcinoma. Mol Med Rep. 2017;16(1):43-48.
  55. Liang Y, Zhang P, Li S, Li H, Song S, Lu B. MicroRNA-873 acts as a tumor suppressor in esophageal cancer by inhibiting differentiated embryonic chondrocyte expressed gene 2. Biomed Pharmacother. 2018;105:582-589.
  56. Li P, Jia YF, Ma XL, et al. DEC2 suppresses tumor proliferation and metastasis by regulating ERK/NF-κB pathway in gastric cancer. Am J Cancer Res. 2016;6(8):1741-57.
  57. Sato F, Kawamura H, Wu Y, et al. The basic helix-loop-helix transcription factor DEC2 inhibits TGF-β-induced tumor progression in human pancreatic cancer BxPC-3 cells. Int J Mol Med. 2012;30(3):495-501.
  58. Nakamura H, Tanimoto K, Hiyama K, et al. Human mismatch repair gene, MLH1, is transcriptionally repressed by the hypoxia-inducible transcription factors, DEC1 and DEC2. Oncogene. 2008;27(30):4200-9.
  59. Chen S, Dong QJ, Wan ZA, Gao S, Tu SL, Chai R. BHLHE41 Overexpression Alleviates the Malignant Behavior of Colon Cancer Cells Induced by Hypoxia via Modulating HIF-1α/EMT Pathway. Gastroenterol Res Pract. 2022;2022:6972331.
  60. Falvella FS, Colombo F, Spinola M, Campiglio M, Pastorino U, Dragani TA. BHLHB3: a candidate tumor suppressor in lung cancer. Oncogene. 2008;27(26):3761-4.
  61. Nagata T, Minami K, Yamamoto M, et al. BHLHE41/DEC2 Expression Induces Autophagic Cell Death in Lung Cancer Cells and Is Associated with Favorable Prognosis for Patients with Lung Adenocarcinoma. Int J Mol Sci. 2021;22(21):11509.
  62. Wang C, Zhao N, Zheng Q, Zhang D, Liu Y. BHLHE41 promotes U87 and U251 cell proliferation via ERK/cyclinD1 signaling pathway. Cancer Manag Res. 2019;11:7657-7672.
  63. Zhou ZH, Wang B, Cheng XB, et al. Roles of SHARP1 in thyroid cancer. Mol Med Rep. 2016; 13(6):5365-71.
  64. Numata A, Kwok HS, Kawasaki A, et al. The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia. Nat Commun. 2018;9(1):1622.
  65. GEPIA2. http://gepia2.cancer-pku.cn. Accessed 19 October 2025.
  66. Ananthasubramaniam B, Venkataramanan R. Rhythm profiling using COFE reveals multi-omic circadian rhythms in human cancers in vivo. PLoS Biol 2025;23(5): e3003196.
  67. Follain G, Dibus M, Joshi O, Jacquemet G. Time, the final frontier. Mol Oncol 2025;29(8):2157-2162.
  68. Chen H, Pan Y, Zhou Q, et al. METTL3 Inhibits Antitumor Immunity by Targeting m6ABHLHE41-CXCL1/CXCR2 Axis to Promote Colorectal Cancer. Gastroenterology 2022;163(4):891-907.
  69. Matsunaga N, Inoue M, Kusunose N, et al. Time-dependent interaction between differentiated embryo chondrocyte-2 and CCAAT/enhancer-binding protein α underlies the circadian expression of CYP2D6 in serum-shocked HepG2 cells. Mol Pharmacol 2012;81(5):739-47.
DOI: https://doi.org/10.62838/amsm-2026-0001 | Journal eISSN: 2668-7763 | Journal ISSN: 2668-7755
Language: English
Page range: 84 - 92
Submitted on: Nov 16, 2025
Accepted on: Jan 26, 2026
Published on: Jul 3, 2026
In partnership with: Paradigm Publishing Services
Publication frequency: 4 issues per year

© 2026 Katalin Csép, published by University of Medicine, Pharmacy, Science and Technology of Targu Mures
This work is licensed under the Creative Commons Attribution 4.0 License.