Cyclin-dependent kinase 6 associates with the androgen receptor and enhances its transcriptional activity in prostate cancer cells

Abstract

Cyclin-dependent kinase 6 (CDK6) binds to and is activated by cyclin D1 and thereby enhances the transition of cells through the G1 phase of the cell cycle. The present study indicates that, in human prostate cancer cells, CDK6 can also bind to the androgen receptor (AR) and stimulate its transcriptional activity in the presence of dihydrotestosterone. This effect of CDK6 does not require its kinase activity and is inhibited by cyclin D1 and p16INK4a. The T877A mutant of the AR frequently found in advanced cases of prostate cancer displays an exaggerated stimulation of transcriptional activity by CDK6. Androgen-sensitive LNCaP prostate cancer cells engineered to stably overexpress CDK6 display increased expression of the prostate-specific antigen and enhanced growth in the presence of dihydrotestosterone. CDK6 is present in the chromatin structure of these cells in association with the AR and the promoter region of the prostate-specific antigen gene. These findings suggest that CDK6 may play an important role in the development and/or progression of a subset of human prostate cancers by stimulating the activity of the AR

Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1

“…It should also be noted that, although Cdk2 and Cdk5 did not enhance AR Ser-81 phosphorylation or expression, other Cdks may contribute to the effects of Cdk antagonists in PCa cells, including possible roles for Cdk7 and Cdk9 in regulating AR message levels. Significantly, previous studies have identified AR interactions with Cdk6 and Cdk7, whereas Cdk2 has been reported to interact with the progesterone receptor (46)(47)(48)(49). We have used Cdk1 siRNA and short hairpin RNA (shRNA) in efforts to further assess the role of Cdk1, but Cdk1 is required for mitosis, and it has not yet been possible to generate Cdk1-depleted PCa cells.…”

The Complex Role of AR Signaling After Cytotoxic Insult: Implications for Cell Cycle Based Chemotherapeutics

“…[34][35][36] In addition, CDK6 negates the ability of cyclin D1 to suppress AR function, and can serve to heighten AR activity independent of it skinase function. 37 In G 2 , CDK1 activity has been shown to promote AR phosphorylation and stabilization, resulting in increased AR activity. 38 Lastly, it was recently shown that AR is degraded in mitosis; although this latter observation was reported to suggest a putative "licensing" function for AR in controlling DNA replication, this concept has yet to be tested.…”

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

“…[35][36][37] CDK6 is overexpressed in lymphoma, leukemia, glioma, glioblastoma, medulloblastoma, and cancers of squamous cells, salivary gland, bladder, pancreas and prostate. [38][39][40][41][42][43][44][45][46][47][48][49][50] In human prostate cancer cells, CDK6 has also been shown to bind androgen receptor and stimulate its activity in a kinase activity independent manner. 46 Blockage of CDK6 expression by microRNAs (miRNAs) has been shown to inhibit the proliferation of gliomas, medulloblastoma, prostate, bladder, gastric, hepatocellular, and lung cancer cells, indicating the significant role of CDK6 in the initiation and progression of these cancers.…”

“…[38][39][40][41][42][43][44][45][46][47][48][49][50] In human prostate cancer cells, CDK6 has also been shown to bind androgen receptor and stimulate its activity in a kinase activity independent manner. 46 Blockage of CDK6 expression by microRNAs (miRNAs) has been shown to inhibit the proliferation of gliomas, medulloblastoma, prostate, bladder, gastric, hepatocellular, and lung cancer cells, indicating the significant role of CDK6 in the initiation and progression of these cancers. [51][52][53][54][55][56][57][58] These observations, coupled with the fact that mice lacking D-type cyclins and/or CDK4/6 are viable, make targeting components of the CDK4/6 cyclin D-INK4-pRb-E2F pathway a highly attractive anti-cancer strategy.…”