Version 1
: Received: 20 July 2024 / Approved: 22 July 2024 / Online: 22 July 2024 (11:52:47 CEST)
How to cite:
Olatunde, D.; De Benedetti, A. The TLK1>Nek1 Axis Promotes Nuclear Retention and Activation of YAP with Implications for CRPC. Preprints2024, 2024071709. https://doi.org/10.20944/preprints202407.1709.v1
Olatunde, D.; De Benedetti, A. The TLK1>Nek1 Axis Promotes Nuclear Retention and Activation of YAP with Implications for CRPC. Preprints 2024, 2024071709. https://doi.org/10.20944/preprints202407.1709.v1
Olatunde, D.; De Benedetti, A. The TLK1>Nek1 Axis Promotes Nuclear Retention and Activation of YAP with Implications for CRPC. Preprints2024, 2024071709. https://doi.org/10.20944/preprints202407.1709.v1
APA Style
Olatunde, D., & De Benedetti, A. (2024). The TLK1>Nek1 Axis Promotes Nuclear Retention and Activation of YAP with Implications for CRPC. Preprints. https://doi.org/10.20944/preprints202407.1709.v1
Chicago/Turabian Style
Olatunde, D. and Arrigo De Benedetti. 2024 "The TLK1>Nek1 Axis Promotes Nuclear Retention and Activation of YAP with Implications for CRPC" Preprints. https://doi.org/10.20944/preprints202407.1709.v1
Abstract
Despite some advances in controlling progression of Prostate Cancer (PCa) that is refractory to the use of ADT/ARSI, most patients eventually succumb to the disease, and there is a pressing need to understand the mechanisms that lead to the development of CRPC. A common mechanism is the ability to integrate AR signals from vanishing levels of testosterone, with the frequent participation of YAP as a coactivator, and pointing to deregulation of the Hippo pathway as a major determinant. We have recently shown that YAP is post-transcriptionally activated via the TLK1>NEK1 axis by a stabilizing phosphorylation at Y407. We are now solidifying this work by showing that: 1) The phosphorylation of Y407 is critical for YAP retention/partition in the nuclei, and that J54 (TLK1i) reverses this along with YAP407 dephosphorylation. 2) That the enhanced degradation of (cytoplasmic) YAP is increased by J54 counteracting its Enzalutamide-induced accumulation. 3) That the basis for all these effects, including YAP nuclear retention, can be explained by the stronger association of pYAP-Y407 with its transcriptional co-activators, AR and TEAD1. 4) We demonstrate that ChIP for GFP-YAP-wt, but hardly for the GFP-YAP-Y407F mutant, at promoters of typical ARE- and TEAD1-driven genes is readily detected but becomes displaced after treatment with J54. 5) While xenografts of LNCaP cells show rapid regression following treatment with ARSI+J54, in the VCaP model, driven by the TMPRSS2-ERG oncogenic translocation, tumors initially respond well to the combination but subsequently recur, despite the continuous suppression of pNek1-T141 and pYAP-Y407. This suggests an alternative parallel pathway for CRPC progression for VCaP tumors long-term, that may be separate from the observed ENZ-driven YAP deregulation, although clearly some YAP gene targets like PD-L1, that are found accumulate following prolonged ENZ treatment, are still suppressed by concomitant addition of J54.
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
