Journal article
Enhancing progestin therapy via HDAC inhibitors in endometrial cancer
American journal of cancer research, Vol.12(11), pp.5029-5048
2022
PMCID: PMC9729913
PMID: 36504895
Abstract
Uterine endometrial cancer (EC) incidence and deaths are on the rise. Hormone therapy, a traditional treatment regimen for this disease, uses progesterone and its synthetic analogue, progestin, to induce cell differentiation, apoptosis, and inhibition of invasion. This therapy is highly effective for progesterone receptor (PR) positive tumors in the short term. However, responsiveness decreases over time due to loss of PR expression; acquired resistance leads to treatment failure and poor prognosis. Primary resistance occurs in advanced, PR-negative tumors. Regardless, progestin therapy can be effective if the PR downregulation mechanism is reversed and if functional PR expression is restored. Using histone deacetylase inhibitors (HDACi), we inhibited cell proliferation in three EC cell lines and restored functional PR expression at the mRNA and protein levels. Two HDACi were tested using an endometrial xenograft tumor model: entinostat, an oral drug, and romidepsin, an IV drug.
and
studies support that entinostat decreased EC tumor growth, induced differentiation, and increased expression of the PR-targeted gene, PAEP. These findings supported the approval of a new NIH NCTN clinical trial, NRG-GY011, which concluded that dual treatment of MPA and entinostat, decreased expression of the proliferation marker, Ki67, but did not increase PR expression relative to single treatment with MPA in this short-term study. Therefore, a more potent HDACi, romidepsin, was investigated. Romidepsin treatment inhibited tumor growth and enhanced progestin treatment efficacy. More importantly, PR, PAEP, and KIAA1324 expressions were upregulated. Using a chromatin immunoprecipitation assay, we verified that HDACi can reverse PR downregulation mechanisms in mice models. Other potential drug efficacy markers, such as CD52, DLK1, GALNT9, and GNG2, were identified by transcriptome analysis and verified by q-PCR. Many of the upregulated drug efficacy markers predict favorable patient outcomes, while downregulated genes predict worse survival. Here, our current data suggests that romidepsin is a more potent HDACi that has the potential to achieve more robust upregulation of PR expression and may be a more promising candidate for future clinical trials.
Details
- Title: Subtitle
- Enhancing progestin therapy via HDAC inhibitors in endometrial cancer
- Creators
- Yiyang Li - First Hospital of Jilin UniversityWei Zhou - Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children Chongqing 401147, ChinaLong Li - First Affiliated Hospital of Xi'an Jiaotong UniversityJohn W Li - Department of Pathology, The University of Iowa Iowa City, IA 52242, USATianyue Li - Department of Pathology, The University of Iowa Iowa City, IA 52242, USACheng Huang - Jiangsu Vocational College of MedicineVanessa J Lazaro-Camp - Department of Pathology, The University of Iowa Iowa City, IA 52242, USATamar Kavlashvili - Vanderbilt University School of MedicineYuping Zhang - University of IowaHenry Reyes - Department of OB/GYN, Division of Gynecologic Oncology, The University at Buffalo NY 14260, USAYujun Li - Department of Obstetrics and Gynecology, The University of Iowa Iowa City, IA 52242, USADonghai Dai - University of IowaWilliam Zhu - Department of Pathology, The University of Iowa Iowa City, IA 52242, USAXiangbing Meng - University of IowaKimberly K Leslie - University of New MexicoShujie Yang - University of Iowa
- Resource Type
- Journal article
- Publication Details
- American journal of cancer research, Vol.12(11), pp.5029-5048
- PMID
- 36504895
- PMCID
- PMC9729913
- ISSN
- 2156-6976
- eISSN
- 2156-6976
- Language
- English
- Date published
- 2022
- Academic Unit
- Pathology; Obstetrics and Gynecology
- Record Identifier
- 9984333160102771
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