Targeting Epigenetic Regulators for Endometrial Cancer Therapy: Its Molecular Biology and Potential Clinical Applications

Inoue, Futaba; Sone, Kenbun; Toyohara, Yusuke; Takahashi, Yu; Kukita, Asako; Hara, Aki; Taguchi, Ayumi; Tsuruga, Tetsushi; Osuga, Yutaka

doi:10.3390/ijms22052305

Cited by 17 publications

(23 citation statements)

References 103 publications

(161 reference statements)

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“…Furthermore, DOT1L activity was reported as a crucial risk factor for the development of cervical cancer associated with the human papilloma virus (HPV) infection ( Liu Y. et al, 2018 ). The employment of epigenetic drug targeting HMTs represents an interesting therapeutic opportunity also in endometrial cancer ( Inoue et al, 2021 . ), but the usefulness of DOT1L inhibition against these tumors still remains to be clarified.…”

Section: Dot1 Prognostic Potential In Solid Tumorsmentioning

confidence: 99%

Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors

et al. 2022

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The histone lysine methyltransferase DOT1L (DOT1-like histone lysine methyltransferase) is responsible for the epigenetic regulation of gene expression through specific methylation of lysine79 residue of histone H3 (H3K79) in actively transcribed genes. Its normal activity is crucial for embryonic development and adult tissues functions, whereas its aberrant functioning is known to contribute to leukemogenesis. DOT1L is the only lysine methyltransferase that does not contain a SET domain, which is a feature that allowed the development of selective DOT1L inhibitors that are currently investigated in Phase I clinical trials for cancer treatment. Recently, abnormal expression of this enzyme has been associated with poor survival and increased aggressiveness of several solid tumors. In this review evidences of aberrant DOT1L expression and activity in breast, ovarian, prostate, colon, and other solid tumors, and its relationships with biological and clinical behavior of the disease and response to therapies, are summarized. Current knowledge of the structural basis of DOT1L ability to regulate cell proliferation, invasion, plasticity and stemness, cell cycle progression, cell-to-cell signaling, epithelial-to-mesenchymal transition, and chemoresistance, through cooperation with several molecular partners including noncoding RNAs, is also reviewed. Finally, available options for the treatment of therapeutically challenging solid tumors by targeting DOT1L are discussed.

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Section: Dot1 Prognostic Potential In Solid Tumorsmentioning

confidence: 99%

Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors

et al. 2022

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“…In addition, KDM1A was also found to demethylate at H3K9me1 and H3K9me2 [ 163 ]. JMJC domain-containing histone demethylases are the highly conserved group that consists of 20 families, including JHDM1, JHDM2 (JMJD1), JHMD3 (JMJD2), JARID, PHF and UT families [ 171 ].…”

Section: Histone Modifications and Ncrnas: The Theorymentioning

confidence: 99%

“…In humans, there are about 30 HATs that are divided into three families: the general control non-depressible 5 (GCN5)-related N-acetyltransferase (GNAT) family (GCN5 and p300/CBP-associated factor (PCAF)), the MYST family (monocytic leukemic zinc factor (MOZ), MOZ-related factor (MOF), Tat interactive protein 60kDa (TIP60) and human acetylase binding to PRC1 (HBO1)) and the p300/CBP family (p300 and CBP). Besides, there are many other nuclear receptors and transcription factors in addition to these HATs [ 171 ].…”

Section: Histone Modifications and Ncrnas: The Theorymentioning

confidence: 99%

“…There are valproic acids, carboxylic acids NaB and short-chain fatty acids, such as phenylbutyrate; hydroxamic acids, including trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA, vorinostat); benzamides, such as entinostat (MS-275) and mocetinostat (MGCD-0103); and cyclic peptides, such as romidepsin (FK228). There are also an increasing number of HDAC inhibitors that have been developed, not included in any group [ 171 ]. Many HDAC inhibitors are non-specific and can be used to inhibit multiple isoforms of HDACs.…”

Section: Histone Modifications and Ncrnas: From Theory To Praxismentioning

confidence: 99%

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Histone Modifications and Non-Coding RNAs: Mutual Epigenetic Regulation and Role in Pathogenesis

Bure

Немцова

Кузнецова

2022

IJMS

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In the last few years, more and more scientists have suggested and confirmed that epigenetic regulators are tightly connected and form a comprehensive network of regulatory pathways and feedback loops. This is particularly interesting for a better understanding of processes that occur in the development and progression of various diseases. Appearing on the preclinical stages of diseases, epigenetic aberrations may be prominent biomarkers. Being dynamic and reversible, epigenetic modifications could become targets for a novel option for therapy. Therefore, in this review, we are focusing on histone modifications and ncRNAs, their mutual regulation, role in cellular processes and potential clinical application.

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“…EC is the 15th most common type of malignant tumor worldwide, and it is the most common gynecological malignant tumor in developed countries ( 2 ). Surgical resection and postoperative adjuvant treatments for EC have been standardized and comprise hysterectomy and bilateral salpingo-oophorectomy, followed by paclitaxel/platinum conventional chemotherapy ( 3 ). However, women with relapsed or advanced disease have a low response rate to conventional treatments and extremely poor clinical outcomes ( 4 , 5 ).…”

Section: Introductionmentioning

confidence: 99%

ZIC2 upregulates lncRNA SNHG12 expression to promote endometrial cancer cell proliferation and migration by activating the Notch signaling pathway

Cai

Li²,

et al. 2021

Mol Med Rep

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It was previously reported that long non-coding RNA (lncRNA) small nucleolar RNA host gene 12 (SNHG12) promoted the proliferation, invasion and migration of endometrial cancer (EC) cells; however, the upstream underlying mechanism remains unclear. The present study aimed to determine the possible underlying mechanism of SNHG12 regulating EC. The Encyclopedia of RNA Interactomes database was used to analyze whether SNHG12 could bind to Zic family member 2 (ZIC2) and the expression levels of ZIC2 in patients with EC. ZIC2 expression levels in EC cell lines were analyzed using western blotting and reverse transcription-quantitative PCR. RL95-2 cells were subsequently transfected with short hairpin RNA targeting ZIC2, or ZIC2 or SNHG12 overexpression plasmids. Cell proliferation, migration and invasion were analyzed using Cell Counting Kit-8, colony formation, wound healing and Transwell assays, respectively. The binding between ZIC2 and SHNG12 was verified using dual luciferase reporter and chromatin immunoprecipitation assays. The results of the present study revealed that the expression levels of ZIC2 were upregulated in the tissues of patients with EC and EC cell lines. ZIC2 knockdown inhibited RL95-2 cell proliferation, migration and invasion. The protein expression levels of Ki67, proliferating cell nuclear antigen, MMP2 and MMP9 were also downregulated following the knockdown of ZIC2. ZIC2 was predicted to bind to SNHG12 and positively regulate SNHG12 expression. Further experiments demonstrated that the effects of the knockdown of ZIC2 on RL95-2 cells were partially reversed by SNHG12 overexpression. In addition, ZIC2 knockdown inhibited Notch signaling activation, while SNHG12 overexpression reversed this effect. In conclusion, the findings of the present study indicated that ZIC2 may upregulate SNHG12 expression to promote EC cell proliferation and migration by activating the Notch signaling pathway.

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Targeting Epigenetic Regulators for Endometrial Cancer Therapy: Its Molecular Biology and Potential Clinical Applications

Cited by 17 publications

References 103 publications

Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors

Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors

Histone Modifications and Non-Coding RNAs: Mutual Epigenetic Regulation and Role in Pathogenesis

ZIC2 upregulates lncRNA SNHG12 expression to promote endometrial cancer cell proliferation and migration by activating the Notch signaling pathway

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