Jae-Hong Kim1,*, Yong-Hak Kim2,*, Hong-Man Kim1, Ho-Oak Park1, Nam-Chul Ha3, Tae Heon Kim4, Mira Park1, Kangseok Lee5 & Jeehyeon Bae1
1 College of Pharmacy, Chung-Ang University, 84 Heukseok-Ro, Dongjak-Gu, Seoul 156-756, Korea. 2 Department of Microbiology, Catholic University of Daegu School of Medicine, 17 Duruegongwon-Ro, Nam-Gu, Daegu 705-718, Korea. 3 Department of Manufacturing Pharmacy, Pusan National University, 63 Busandaehak-Ro, Kumjeong-Gu, Busan 609-735, Korea. 4 Department of Pathology, CHA University, 59 Yatap-Ro, Bundang-Gu, Seongnam 463-836, Korea. 5 Department of Life Science, Chung-Ang University, 84 Heukseok-Ro, Dongjak-Gu, Seoul 156-756, Korea.
* These authors contributed equally to this work.
Correspondence to: Kangseok Lee or Jeehyeon Bae
Approximately 97% of patients with ovarian granulosa cell tumours (GCTs) bear the C134W mutation in FOXL2; however, the pathophysiological mechanism of this mutation is unknown. Here we report how this mutation affects GCT development. Sequential posttranslational modifications of the C134W mutant occur where hyperphosphorylation at serine 33 (S33) by GSK3β induces MDM2-mediated ubiquitination and proteasomal degradation. In contrast, S33 of wild-type FOXL2 is underphosphorylated, leading to its SUMOylation and stabilization. This prominent hyperphosphorylation is also observed at S33 of FOXL2 in GCT patients bearing the C134W mutation. In xenograft mice, the S33 phosphorylation status correlates with the oncogenicity of FOXL2, and the inhibition of GSK3β efficiently represses GCT growth. These findings reveal a previously unidentified regulatory mechanism that determines the oncogenic attributes of the C134W mutation via differential posttranslational modifications of FOXL2 in GCT development.