Vcp/P97 Segregase-Mediated Regulation Of Chromatin-Bound Pten Stability

Phosphatase and Tensin homolog (PTEN) tumor suppressor protein is associated with many human cancers. PTEN has been shown to accumulate in the nucleus and control DNA repair in response to genotoxic stress. PTEN down-regulation impairs the capacity of global genomic nucleotide excision repair by suppressing the early DNA damage sensor, Xeroderma pigmentosum C (XPC), protein. Our recent work has demonstrated that the Valosin-containing protein (VCP)/p97 segregase participates in proteolytic processing of XPC and Cockayne syndrome B (CSB) proteins. Here, we show that (i) VCP/p97 segregase, in conjunction with its adaptor proteins, specifically extracts PTEN from damaged chromatin for targeted proteasomal degradation, (ii) inhibition of VCP/p97 activity induces the accumulation of PTEN on chromatin, and (iii) VCP/p97 physically interacts with PTEN. Depletion of VCP/p97, in p97-knockout cells or siRNA-mediated ablation in normal cells, affects the stability of PTEN in response to cellular UV irradiation. Results show that compromising the proteasome and VCP/p97 functions causes the accumulation of PTEN accompanied by an increase of UBXD7, proteasomal RPN2 and Sug1 within the chromatin compartment. To our knowledge, this is the first report to reveal that VCP/p97 segregase extracts tumor suppressor PTEN from damaged chromatin. (This work was supported by NIH grants ES002388 and ES012991 to AAW). Citation Format: Jinshan He, Gulzar Wani, Qianzheng Zhu, Altaf A Wani. VCP/p97 segregase-mediated regulation of chromatin-bound PTEN stability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2565. doi:10.1158/1538-7445.AM2017-2565