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An Essential Role of the HIF‐1α–c‐Myc Axis in Malignant Progression
Author(s) -
Yoo YoungGun,
Hayashi Masami,
Christensen Jared,
Huang L. Eric
Publication year - 2009
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2009.05043.x
Subject(s) - transactivation , cancer research , biology , transcription factor , psychological repression , gene , tumor progression , dna repair , apoptosis , transcription (linguistics) , dna damage , promoter , genome instability , dna , microbiology and biotechnology , genetics , gene expression , linguistics , philosophy
Cancer is a disease of genomic aberration. The hypoxic microenvironment is believed to promote tumor progression via the induction of genetic instability. To understand how hypoxia drives tumor progression, we have shown recently that the hypoxia‐inducible transcription factor, HIF‐1α, is critical for transcriptional repression of DNA repair genes by a noncanonical mode of action referred to as the “HIF‐1α–c‐Myc axis.” HIF‐1α action via the HIF‐1α–c‐Myc axis is independent of its DNA‐binding and transactivation domains; instead it requires the PAS‐B domain to displace the transcription activator c‐Myc from the target gene promoter for gene repression. Owing to the functional compromise on DNA repair, tumor cells with activated HIF‐1α–c‐Myc axis display persistent DNA damage, genetic alterations, and malignant progression. However, apoptosis‐proficient cells are resistant to such changes. These findings argue that the hypoxic microenvironment plays a critical role in driving genetic alterations especially in apoptosis‐deficient cells for malignant progression.