Abstract
Endometrial cancer (EC) is the most common gynecological malignancy worldwide. However, the molecular mechanisms underlying EC progression are still largely unknown, and chemotherapeutic options for EC patients are currently very limited. In this study, we found that histone methyltransferase EZH2 and DNA methyltransferase DNMT3B were upregulated in EC samples from patients, and promoted EC cell proliferation as evidenced by assays of cell viability, cell cycle, colony formation. Mechanistically, we found that EZH2 promoted EC cell proliferation by epigenetically repressing TCF3, a direct transcriptional activator of CCKN1A (p21WAF1/Cip1), in vitro and in vivo. In addition, we found that DNMT3B specifically methylated the TCF3 promoter, repressing TCF3 expression and accelerating EC cell proliferation independently of EZH2. Importantly, elevated expression of EZH2 or DNMT3B in EC patients inversely correlated with expression of TCF3 and p21, and was associated with shorter overall survival. We show that combined treatment with GSK126 and 5-Aza-2d treatment wit synergistically inhibited methyltransferase activity of EZH2 and DNMT3B, resulting in a profound block of EC cell proliferation as well as EC tumor progression in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. These findings reveal that TCF3 functions as a tumor suppressor epigenetically silenced by EZH2 and DNMT3B in EC, and support the notion that targeting the EZH2/DNMT3B/TCF3/p21 axis may be a novel and effective therapeutic strategy for treatment of EC.
Highlights
Endometrial cancer (EC) is the most common gynecological malignancy worldwide, with over 61,880 new cases and nearly 12,160 deaths estimated in 2019 in the United States [1]
These results are consistent with meta-analysis of transcriptome data extracted from The Cancer Genome Atlas (TCGA) Data Portal which show that enhancer of zeste homolog 2 (EZH2) mRNA levels in EC patient tumor tissues were significantly higher than adjacent normal tissues (Supplementary Fig. S1B)
TCF3 is a direct target of EZH2 which acts as a tumor suppressor in EC cells Given that EZH2 might regulate, indirectly, transcription of p21, we reasoned that there was a transcription factor or other molecule that were regulated by EZH2 directly to bridge the gap between EZH2 and p21
Summary
Endometrial cancer (EC) is the most common gynecological malignancy worldwide, with over 61,880 new cases and nearly 12,160 deaths estimated in 2019 in the United States [1] Owing to their aggressive characteristics, serious ECs have high recurrence rates, and are associated with high mortality, having very poor fiveyear survival rates of less than 30% [1, 2]. To date, chemotherapeutic options for EC patients have been limited; FDA-approved targeted therapies for ECs include hormonal intervention (for hormone-dependent endometrioid ECs), the immune checkpoint inhibitor, pembrolizumab, and recently the combination of pembrolizumab with lenvatinib for the treatment of a special category of advanced ECs [4, 5] In view of these limited options for targeted regimes for treating ECs, there is an urgency for revising and improving therapies for EC. The roles of EZH2 and DNMT3B and underlying molecular mechanisms for malignant transformation and cell proliferation in EC remain largely unknown, increased EZH2 and DNMT3B expressions have been shown in EC tissues [11,12,13,14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
