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Published on: January 11, 2019
KLHL29-mediated DDX3X degradation promotes chemosensitivity by abrogating cell cycle checkpoint in triple-negative
Litong Yao1, Qian Hao2, Mozhi Wang1
1Department of Breast Surgery, the First Hospital of China Medical University, Shenyang, Liaoning, China.
Abstract:
Triple-negative breast cancer (TNBC) is a heterogeneous breast cancer subtype and accounts for approximately 15-20% of breast cancer cases. In this study, we identified KLHL29, which is an understudied member of the Kelch-like gene family, as a crucial tumor suppressor that regulates chemosensitivity in TNBC. KLHL29 expression was significantly downregulated in breast cancer tissues compared with adjacent normal tissues, and low levels of KLHL29 were associated with unfavorable prognoses. Ectopic KLHL29 suppressed, while depleting KLHL29 promoted, the growth, proliferation, migration, and invasion of TNBC. Mechanistically, KLHL29 recruited the CUL3 E3-ligase to the RNA-binding protein DDX3X, leading to the proteasomal degradation of the latter. This downregulation of DDX3X resulted in the destabilization of CCND1 mRNA and the consequent cell cycle arrest at G0/G1 phase. Remarkably, the DDX3X inhibitor RK33 combined with platinum-based chemotherapy can synergistically suppress TNBC that usually expresses low levels of KLHL29 and high levels of DDX3X using cancer cell-derived xenograft and patient-derived organoids models. Altogether, we uncovered the potential role for the KLHL29-DDX3X signaling cascade in the regulation of TNBC progression, thus providing a promising combination strategy for overcoming TNBC chemoresistance.
Insights
Triple-negative breast cancer (TNBC) is a heterogeneous subtype. This study identifies KLHL29 as a tumor suppressor regulating chemosensitivity by degrading DDX3X, offering a new therapeutic strategy for TNBC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options.
- KLHL29, a Kelch-like gene family member, is understudied in cancer.
- Tumor suppressors regulating chemosensitivity are critical for TNBC treatment.
Purpose of the Study:
- To investigate the role of KLHL29 in triple-negative breast cancer.
- To elucidate the molecular mechanism by which KLHL29 affects TNBC progression and chemosensitivity.
- To explore novel therapeutic strategies for TNBC based on the KLHL29 pathway.
Main Methods:
- Analysis of KLHL29 expression in breast cancer tissues and correlation with prognosis.
- In vitro studies assessing the effects of KLHL29 manipulation on TNBC cell behavior.
- Mechanistic studies involving protein-protein interactions, ubiquitination, and mRNA degradation.
- In vivo evaluation of combination therapy using xenograft and patient-derived organoid models.
Main Results:
- KLHL29 expression is downregulated in TNBC and associated with poor prognosis.
- KLHL29 suppresses TNBC growth, migration, and invasion.
- KLHL29 promotes DDX3X proteasomal degradation via CUL3 E3-ligase recruitment, destabilizing CCND1 mRNA and causing G0/G1 cell cycle arrest.
- Combined treatment with DDX3X inhibitor RK33 and platinum-based chemotherapy synergistically inhibits TNBC growth in preclinical models.
Conclusions:
- KLHL29 acts as a tumor suppressor in TNBC by regulating the KLHL29-DDX3X signaling cascade.
- The KLHL29-DDX3X pathway is a potential therapeutic target for TNBC.
- Combination therapy targeting DDX3X and chemotherapy shows promise for overcoming TNBC chemoresistance.
