13q22.1

BTEB2,CKLF,IKLF

Breast cancer

The KLF5 gene is deleted in about 43% breast cancer cell lines. Consistently, KLF5 mRNA is down-regulated in these cell lines. In 9 breast cancer cell lines without KLF5 mRNA loss, KLF5 protein is excessively degraded through ubiquitin-proteasome pathway. Forced expression of KLF5 inhibits T-47D cancer cell growth in vitro. In contrast, KLF5 expression is upregulated in clinical breast tumor samples (see below)

Recently, high level of KLF5 mRNA expression is found to be associated with shorter survival for breast cancer patients. Using tissue microarray, we performed immunohistochemical staining with the anti-KLF5 Ab. The results suggest that KLF5 protein is generally weak in normal breast epithelial cells but strongly positive in breast tumors. Therefore, KLF5 expression is probably a good prognosis marker for breast cancer.

Prostate cancer

The KLF5 gene is deleted in about 33% prostate cancer cell lines/xenografts. Consistently, KLF5 mRNA is down-regulated in these samples compared to three immortalized prostate epithelial cell lines. In PC-3 prostate cancer cell line in which KLF5 mRNA is at normal high level, KLF5 protein is excessively degraded by over-expression of WWP1. KLF5 protein is highly expressed in normal prostate epithelial cells (Figure 5). Forced expression of KLF5 inhibits DU145 and 22Rv1 prostate cancer cell growth in vitro. In contrast, KLF5 knock-down decreases RWPE1 immortalized prostate epithelial cell growth in vitro. These results suggest that KLF5 may play a context dependent role in prostate cancer.

Bladder cancer

KLF5 mRNA is down-regulated in several bladder cancer cell lines. In TSu-Pr1 cell line, KLF5 over-expression promotes tumorigenesis in SCID mice. Consistently, KLF5 promotes cell cycle progression from G1 to S phase. Interestingly, KLF5 appears to promote tumor angiogenesis. Microarray analysis identified a number of angiogenic factors that are potentially regulated by KLF5, including HBP17, TGFa, and PDGFa. These findings suggest that the KLF5 transcription factor may play an oncogenic role in bladder cancer.

Intestinal and colon cancer

Down-regulation of KLF5 may be an early event in intestinal tumorigenesis. Expression of KLF5 in non-transformed intestinal epithelial cells enhances cell growth; however, KLF5 inhibits cell growth in colon cancer cell lines. Another group found that all-trans retinoic acid inhibits intestinal epithelial cell growth in vitro through inhibiting KLF5 expression. At the same time, lipopolysaccharide (LPS) induces proinflammatory response in intestinal epithelial cells through inducing KLF5 expression. These findings suggest that KLF5 may play an important but yet to be identified role in intestinal and colon cancer.

Esophagus cancer

KLF5 is expressed in proliferating cells of the gastrointestinal tract, including the esophagus. Expression of KLF5 in a poorly differentiated esophageal squamous cancer cell line TE2 inhibits proliferation and invasion, decreases viability after treatment with hydrogen peroxide and UV irradiation, and increases anoikis. KLF5 upregulates the cdk inhibitor p21(waf1/cip1) and pro-apoptotic protein BAX following UV irradiation.

Skin cancer

KLF5 is expressed predominantly in the basal layers of the developing epidermis, in the basal layers of cells of the inner root sheath, and in matrix cells of adult human hair follicles. In a transgenic mouse model, KLF5 over-expression in the basal layers of the epidermis causes abnormal epidermal development and differentiation. KLF5 over-expression may decrease the proliferation of stem cell populations of bulge keratinocytes.

Cardiovascular remodeling

KLF5 hemizygous knock-out mice reduce cardiac hypertrophy and interstitial fibrosis upon infusion of angiotensin II. Additionally, KLF5 may play a role in antherosclerosis and restenosis through regulating vascular smooth muscle cells.