![]() To define the prevalence of KLF5 superenhancer amplification across cancers, we examined SNP array–based copy-number data targeting the ∼600 kb intergenic region between KLF5 and KLF12 on chromosome segment 13q22.1 across 10,844 samples from 33 cancer types included in The Cancer Genome Atlas (TCGA). ![]() In noncoding regions, somatic mutations are known to increase the activity of distal enhancers or super-enhancers to activate ESR1 and TAL1 expression ( 18, 19). In addition, somatic single-nucleotide variants (SNV) can activate oncogenic transcription factors for example, missense mutations in the degron domains of NFE2L2 stabilize the protein by preventing its binding to the E3 ubiquitin ligase KEAP1 ( 16, 17). For example, somatic structural variations such as copy-number amplifications increase gene dosage of MYC, MYCN, AR, MITF, and SOX2 and upregulate their expression ( 1–6) chromosomal translocations can place regulatory elements such as enhancers or super-enhancers adjacent to oncogenes and activate their expression, as observed with MYC, MYB, and ERG ( 7–12) whereas amplification of noncoding superenhancers is known to activate MYC ( 13–15). Genomic alterations during tumorigenesis can lead to the activation of oncogenic transcription factors, resulting in aberrant gene regulation throughout the genome. This article is highlighted in the In This Issue feature, p. Significance: Our observations, together with previous studies that identified oncogenic properties of KLF5, establish the importance of KLF5 activation in human cancers, delineate the varied genomic mechanisms underlying this occurrence, and nominate KLF5 as a putative target for therapeutic intervention in cancer. Utilizing data from CRISPR/Cas9 gene knockout screening, we reveal that cancer cells with KLF5 overexpression are dependent on KLF5 for their proliferation, suggesting KLF5 as a putative therapeutic target. Here, we show that these alterations activate KLF5 by three distinct mechanisms: (i) Focal amplification of superenhancers activates KLF5 expression in squamous cell carcinomas (ii) Missense mutations disrupt KLF5–FBXW7 interactions to increase KLF5 protein stability in colorectal cancer (iii) Cancer type–specific hotspot mutations within a zinc-finger DNA binding domain of KLF5 change its DNA binding specificity and reshape cellular transcription. We recently reported that the KLF5 gene is also subject to other types of somatic coding and noncoding genomic alterations in diverse cancer types. Krüppel-like factor 5 gene ( KLF5) has been shown to promote cancer cell proliferation and tumorigenesis and to be genomically amplified in cancer cells. The Krüppel-like family of transcription factors plays critical roles in human development and is associated with cancer pathogenesis.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |