p21WAF1/Cip1 Regulation by hYSK1 Activates SP-1 Transcription Factor and Increases MMP-2 Expression under Hypoxic Conditions

Abstract

The hYSK1, a serine/threonine kinase (STK)-25, has been implicated in a variety of cellular functions including cell migration and polarity. We have recently reported that hYSK1 down-regulated the expression and functions of p16INK4a, a cell cycle regulatory protein, thereby enhancing migration and growth of cancer cells under hypoxic conditions. In this study, we further investigated the mechanisms underlying downregulation of p16INK4a and anti-migratory function of hYSK1. Our study revealed that p21WAF1/Cip1 is a novel binding partner of hYSK1. Moreover, the interaction between hYSK1 and p21WAF1/Cip1 led to the inhibition of SP-1 transcriptional activity, as revealed by a significant down-regulation of SP-1-mediated transactivation of p16INK4a promoter, and accelerated MMP-2 expression. Conversely, the knock-down of hYSK1 enhanced the p16INK4a promoter activity and protein expression, and diminished MMP-2 transcription and protein levels in hypoxic conditions as compared to control. Taken together, hYSK1 blocks the p21WAF1/Cip1 functions by direct interaction and inhibits the p16INK4a expression and induces MMP-2 expression by its regulations of SP-1 transcriptional activity under the hypoxia conditions.

Downregulation of STK25 promotes autophagy via the Janus kinase 2/signal transducer and activator of transcription 3 pathway in colorectal cancer

“…19 Lee et al revealed that STK25 increased cancer cells proliferation and migration under hypoxic condition through the interaction of STK25 with p21 WAF1/Cip1 to inhibit p16 INK4a promoter activity and increase the expression of MMP-2. 20 However, Lim et al suggested that loss of STK25 promoted the proliferation of tumor cells through the inactivation of the Hippo signaling pathway. 21 Patients with high STK25 expression in neuroblastoma are correlated with a favorable prognosis.…”

“…The study by Zhang et al demonstrated higher STK25 expression in prostate cancer tissues than in benign prostatic hyperplasia, which is involved in prostate tumorigenesis 19 . Lee et al revealed that STK25 increased cancer cells proliferation and migration under hypoxic condition through the interaction of STK25 with p21 WAF1/Cip1 to inhibit p16 INK4a promoter activity and increase the expression of MMP‐2 20 . However, Lim et al suggested that loss of STK25 promoted the proliferation of tumor cells through the inactivation of the Hippo signaling pathway 21 .…”

“…STK25 is highly expressed in prostate cancer tissues and has been implicated in prostate carcinogenesis 19 . Under the condition of hypoxia, STK25 increased cancer cells proliferation and migration 20 . However, loss of STK25 may promote tumorigenesis and disease progression through inhibition of the Hippo pathway 21 .…”

“…19 Under the condition of hypoxia, STK25 increased cancer cells proliferation and migration. 20 However, loss of STK25 may promote tumorigenesis and disease progression through inhibition of the Hippo pathway. 21 Moreover, in neuroblastoma, high expression of STK25 indicated a favorable prognosis, and STK25 functions as a responder of the death signaling.…”

STK25: a viable therapeutic target for cancer treatments?

“…Furthermore, STK25 seems to have distinctly different functions in stressed cells and non-stressed cells, regulating cell death of the former [11]. Lee et al [12] reported that STK25 suppresses the expression and function of p16 INK4a , a cell cycle regulatory protein, thereby increasing the migration and proliferation of cancer cells under hypoxic conditions.…”