The long isoform of FABP6 facilitates WWP2-mediated PTEN ubiquitination to activate AKT/mTOR signalling and contributes to reduced everolimus sensitivity in clear cell renal cell carcinoma.
- 1Department of Urology, Peking University Third Hospital, Beijing, China.
- 2Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
- 3Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing, China.
Abstract
How PTEN function is impaired in clear cell renal cell carcinoma (ccRCC) without detectable genomic alterations remains unresolved. We investigated whether the long isoform of fatty acid-binding protein 6 (FABP6L) contributes to this process. Analyses that distinguished FABP6 isoforms identified FABP6L as the principal tumour-upregulated variant, whereas the short isoform, FABP6S, did not show a comparable increase. SHOX2 depletion preferentially reduced FABP6L expression. Biochemical experiments linked FABP6L to increased association between PTEN and the E3 ligase WWP2, enhanced PTEN polyubiquitination, and reduced PTEN protein stability. These changes were accompanied by increased AKT/mTOR signalling. Gain- and loss-of-function experiments supported a growth-promoting role for FABP6L in cultured ccRCC cells and xenografts, while genetic rescue experiments indicated a major contribution of PTEN to the signalling and growth phenotypes. In preclinical models with reduced everolimus sensitivity, FABP6L depletion increased PTEN abundance and enhanced the response to mTOR inhibition. The findings support an isoform-specific mechanism connecting FABP6L to PTEN turnover and ccRCC growth. They also provide a basis for investigating FABP6L-directed approaches to improve everolimus response, although their clinical relevance requires further validation.
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BibTeX
@article{yin2026long,
title = {{The long isoform of FABP6 facilitates WWP2-mediated PTEN ubiquitination to activate AKT/mTOR signalling and contributes to reduced everolimus sensitivity in clear cell renal cell carcinoma.}},
author = {Haoming Yin and Zijie Wang and Liyuan Ge and Wei Liu and Fan Shu and Ye Yan and Hui Liang and Shudong Zhang},
journal = {Clinical and translational medicine},
year = {2026},
month = oct,
doi = {10.1002/ctm2.70880},
url = {https://europepmc.org/article/MED/42926320},
note = {CC BY},
}
RIS
TY - JOUR
TI - The long isoform of FABP6 facilitates WWP2-mediated PTEN ubiquitination to activate AKT/mTOR signalling and contributes to reduced everolimus sensitivity in clear cell renal cell carcinoma.
AU - Haoming Yin
AU - Zijie Wang
AU - Liyuan Ge
AU - Wei Liu
AU - Fan Shu
AU - Ye Yan
AU - Hui Liang
AU - Shudong Zhang
PY - 2026
DA - 2026/10/01
JO - Clinical and translational medicine
DO - 10.1002/ctm2.70880
UR - https://europepmc.org/article/MED/42926320
AB - How PTEN function is impaired in clear cell renal cell carcinoma (ccRCC) without detectable genomic alterations remains unresolved. We investigated whether the long isoform of fatty acid-binding protein 6 (FABP6L) contributes to this process. Analyses that distinguished FABP6 isoforms identified FABP6L as the principal tumour-upregulated variant, whereas the short isoform, FABP6S, did not show a comparable increase. SHOX2 depletion preferentially reduced FABP6L expression. Biochemical experiments linked FABP6L to increased association between PTEN and the E3 ligase WWP2, enhanced PTEN polyubiquitination, and reduced PTEN protein stability. These changes were accompanied by increased AKT/mTOR signalling. Gain- and loss-of-function experiments supported a growth-promoting role for FABP6L in cultured ccRCC cells and xenografts, while genetic rescue experiments indicated a major contribution of PTEN to the signalling and growth phenotypes. In preclinical models with reduced everolimus sensitivity, FABP6L depletion increased PTEN abundance and enhanced the response to mTOR inhibition. The findings support an isoform-specific mechanism connecting FABP6L to PTEN turnover and ccRCC growth. They also provide a basis for investigating FABP6L-directed approaches to improve everolimus response, although their clinical relevance requires further validation.
SN - 2001-1326
ER -