Prostate Cancer Metastasis Requires Loss of E-Cadherin Activity

Cancer researchers have shown how the action of the transcription factor SPDEF (SAM Pointed Domain ETS transcription Factor) regulates E-Cadherin in prostate cancer cells and determines whether the prostate tumor will metastasize.

Cadherins (named for “calcium-dependent adhesion”) are a class of type-1 transmembrane proteins. They play important roles in cell adhesion, ensuring that cells within tissues are bound together. They are dependent on calcium (Ca2+) ions to function, hence their name. It has been observed that cells containing a specific cadherin subtype tend to cluster together to the exclusion of other types, both in cell culture and during development. Loss of E-cadherin function or expression has been implicated in cancer progression and metastasis. E-cadherin down regulation decreases the strength of cellular adhesion within a tissue, resulting in an increase in cellular motility. This in turn may allow cancer cells to cross the basement membrane and invade surrounding tissues.

The SPDEF protein belongs to the ETS family of transcription factors. It is highly expressed in prostate epithelial cells and functions as an androgen-independent transactivator of prostate-specific antigen (PSA) promoter.

Investigators at the University of Colorado Cancer Center (Denver, USA) had shown previously that SPDEF inhibited prostate cancer metastasis in vitro and in vivo. In the present study, they evaluated the relationship between SPDEF and E-Cadherin expression in an effort to better understand the mechanism of action of SPDEF in prostate tumor-cell invasion and metastasis.

Results published in the February 28, 2013, online edition of the Journal of Biological Chemistry demonstrated a direct correlation between expression of E-Cadherin and SPDEF in prostate cancer cells and showed that modulation of E-Cadherin and SPDEF had similar effects on cell migration and invasion. In addition, short interfering RNA (siRNA) mediated knockdown of E-Cadherin was sufficient to block the effects of SPDEF on cell migration and invasion. Stable forced expression of SPDEF resulted in increased expression of E-Cadherin, while down regulation of SPDEF decreased E-Cadherin expression. SPDEF expression was not regulated by E-Cadherin.

A chromatin immuno-precipitation and luciferase reporter assay revealed that SPDEF occupied the E-Cadherin promoter site and acted as a direct transcriptional inducer of E-Cadherin in prostate cancer cells.

“When E-Cadherin is lost, cells become rogue: they can detach from their surrounding tissues, move effortlessly through the circulatory system, grow and attach at new sites,” said senior author Dr. Hari Koul, professor of urology at the University of Colorado Cancer Center. “In prostate tumors that had lost E-Cadherin, we put in SPDEF and the tumors once again expressed E-Cadherin. They were once again anchored in place and unable to metastasize. We can make these rogue cells back into epithelial-like cells and these epithelial cells stay anchored and lose the ability to migrate.”

“These studies paint a pretty compelling picture of SPDEF working in part through the modulation of E-Cadherin to inhibit prostate cancer metastasis,” said Dr. Koul. “To the best of our knowledge these are the first studies demonstrating the requirement of SPDEF for expression of E-Cadherin. This could be a real landmark. We see a prerequisite for metastasis and now we have a very clear picture of how to remove this necessary condition for the most dangerous behavior of prostate cancer.”

Related Links:
University of Colorado Cancer Center