Abstract
While many genes specifically act as oncogenes or tumor suppressors, others are tumor promoters or suppressors in a context-dependent manner. Here we will review the basic-helix-loop-helix (BHLH) protein BHLHE40, (also known as BHLHB2, STRA13, DEC1, or SHARP2) which is overexpressed in gastric, breast, and brain tumors; and downregulated in colorectal, esophageal, pancreatic and lung cancer. As a transcription factor, BHLHE40 is expressed in the nucleus, where it binds to target gene promoters containing the E-box hexanucleotide sequence, but can also be expressed in the cytoplasm, where it stabilizes cyclin E, preventing cyclin E-mediated DNA replication and cell cycle progression. In different organs BHLHE40 regulates different targets; hence may have different impacts on tumorigenesis. BHLHE40 promotes PI3K/Akt/mTOR activation in breast cancer, activating tumor progression, but suppresses STAT1 expression in clear cell carcinoma, triggering tumor suppression. Target specificity likely depends on cooperation with other transcription factors. BHLHE40 is activated in lung and esophageal carcinoma by the tumor suppressor p53 inducing senescence and suppressing tumor growth, but is also activated under hypoxic conditions by HIF-1α in gastric cancer and hepatocellular carcinomas, stimulating tumor progression. Thus, BHLHE40 is a multi-functional protein that mediates the promotion or suppression of cancer in a context dependent manner.
Highlights
The study of the biology of cancer identified many oncogenes such as the transcription factor c-myc [1], the regulatory GTP-binding protein Ras [2], and the receptor tyrosine kinase epidermal growth factor receptor (EGFR) [3]
We discuss the role of basic helix-loop-helix protein 40 (BHLHE40) in oncogenesis, since it is overexpressed in some cancers and suppressed in others
We conclude that BHLHE40 overexpression does not always indicate increased activity, such as in breast cancer, where it is expressed in the cytoplasm, suppressing cell growth by stabilizing cyclin E
Summary
The study of the biology of cancer identified many oncogenes such as the transcription factor c-myc [1], the regulatory GTP-binding protein Ras [2], and the receptor tyrosine kinase epidermal growth factor receptor (EGFR) [3]. BHLHE40 is regulated by a number of important www.Genes&Cancer.com signaling pathways and transcription factors, such as TGFβ, hypoxia inducible factor (HIF), CLOCK-BMAL1 heterodimers and RORα [36,37,38,39]. These studies demonstrate that in all subtypes of www.Genes&Cancer.com brain carcinoma, tumor aggression is associated with an increase in the expression of BHLHE40.
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