miR-129 regulates cell proliferation by downregulating Cdk6 expression

Abstract

Reduced expression of miR-129 has been reported in multiple tumor cell lines and in primary tumors including medulloblastoma, undifferentiated gastric cancers, lung adenocarcinoma, endometrial cancer and colorectal carcinoma. There is also recent evidence of an anti-proliferative activity of miR-129 in tumor cell lines. Still, little is known about how miR-129 regulates cell proliferation. Here we found that lentiviral-mediated overexpression of miR-129 in mouse lung epithelial cells (E10 cells) results in significant G(1) phase arrest that eventually leads to cell death. miR-129 induce G(1) phase arrest in multiple human lung adenocarcinoma cell lines, suggesting miR-129 targeting of G(1)/S phase-specific regulators. Interestingly, we show that Cdk6, a kinase involved in G(1)-S transition, is a direct target of miR-129. We also found the downregulation of three other cell cycle-related novel targets of miR-129, including Erk1, Erk2 and protein kinase C epsilon (Prkce). We further show that among these targets, only Cdk6 is functionally relevant. Restoring expression of Cdk6, but not Prkce partially rescues the cell growth arrest and cell death phenotype that results from miR-129 overexpression. Together, our data indicate that miR-129 plays an important role in regulating cell proliferation by downregulation of Cdk6.

Macro-management of microRNAs in cell cycle progression of tumor cells and its implications in anti-cancer therapy

“…One example is cyclin D1, which is regulated by miR449a [35] , miR-193b [36] , miR-15/16 [37][38][39] , miR-19a [40] , miR-195 [41] , and miR-302a [42] . The cyclin D1 binding proteins CDK4 and CDK6 are also regulated by a number of miRNAs, including miR-107 [43] , miR-449a [44] , miR-129 [45] , miR-125b [46] , miR-15/16 [39] , miR-24 [47] , miR-195 [41] , and miR-124a [48] . Another important G 1 /S regulator cyclin E, is down-regulated by miR-16 [37] and miR-195 [49] .…”

Targeting CDK6 in cancer: State of the art and new insights

“…48,71 Interfering with the production of CDK6 by shRNA or by inducing specific miRNA (i.e., miR-124) reduced proliferation and colony formation in vitro and inhibited the growth of medulloblastoma xenograft tumors in animals. 47,54,72 More recently, PD0332991 has been shown to arrest cells in the G1 phase, decrease proliferation and sensitize medulloblastoma cells to ionizing radiation; the effects being modulated by its CDK6 inhibitory mechanism. As alterations in CDK4, cyclin D1, p15 and p16 genes are not commonly seen in medulloblastoma, 73 targeting CDK6 specifically may prove beneficial in treating medulloblastoma with minimal toxicity.…”

Aberrant hypermethylation ofmiR-9genes in gastric cancer

“…[2][3][4] Previous studies have shown that many miRNAs are aberrantly overexpressed or downregulated during gastric cancer progression, including miR- 16, miR-21, miR-101, miR-126, miR-129, miR-181c, miR-196b and -200. [5][6][7][8][9][10][11][12] These miRNAs could play oncogenic or tumor-suppressive functions in the regulation of cell growth, apoptosis and cell migration by repressing their target genes.…”