Targeting epigenetic modifications in cancer therapy: erasing the roadmap to cancer

Mohammad, Helai P.; Barbash, Olena; Creasy, Caretha L.

doi:10.1038/s41591-019-0376-8

Cited by 318 publications

(219 citation statements)

References 207 publications

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“…Epigenetic regulation is deeply involved in the genesis and development of cancer cells [35][36][37]. Among the complex regulatory networks, lncRNAs play a crucial role in affecting the fate of tumors [38][39][40][41].…”

Section: Discussionmentioning

confidence: 99%

LncRNA LINRIS stabilizes IGF2BP2 and promotes the aerobic glycolysis in colorectal cancer

et al. 2019

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Background: Long noncoding RNAs (lncRNAs) play nonnegligible roles in the epigenetic regulation of cancer cells. This study aimed to identify a specific lncRNA that promotes the colorectal cancer (CRC) progression and could be a potential therapeutic target. Methods:We screened highly expressed lncRNAs in human CRC samples compared with their matched adjacent normal tissues. The proteins that interact with LINRIS (Long Intergenic Noncoding RNA for IGF2BP2 Stability) were confirmed by RNA pull-down and RNA immunoprecipitation (RIP) assays. The proliferation and metabolic alteration of CRC cells with LINRIS inhibited were tested in vitro and in vivo.Results: LINRIS was upregulated in CRC tissues from patients with poor overall survival (OS), and LINRIS inhibition led to the impaired CRC cell line growth. Moreover, knockdown of LINRIS resulted in a decreased level of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), a newly found N 6 -methyladenosine (m 6 A) 'reader'. LINRIS blocked K139 ubiquitination of IGF2BP2, maintaining its stability. This process prevented the degradation of IGF2BP2 through the autophagy-lysosome pathway (ALP). Therefore, knockdown of LINRIS attenuated the downstream effects of IGF2BP2, especially MYC-mediated glycolysis in CRC cells. In addition, the transcription of LINRIS could be inhibited by GATA3 in CRC cells. In vivo experiments showed that the inhibition of LINRIS suppressed the proliferation of tumors in orthotopic models and in patient-derived xenograft (PDX) models.Conclusion: LINRIS is an independent prognostic biomarker for CRC. The LINRIS-IGF2BP2-MYC axis promotes the progression of CRC and is a promising therapeutic target.

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Section: Discussionmentioning

confidence: 99%

LncRNA LINRIS stabilizes IGF2BP2 and promotes the aerobic glycolysis in colorectal cancer

et al. 2019

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“…These include EZH2, DNA methylation, and noncoding RNAs. Reversal of epigenetic alteration is considered to be a promising strategy for cancer treatment [51]. Extensive efforts have been made to identify the promoter methylation profile in USC.…”

Section: Epigenetic Alterationsmentioning

confidence: 99%

Pathogenesis and Clinical Management of Uterine Serous Carcinoma

Zhang

Kwan

Wong

et al. 2020

Cancers

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Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer that has not been well characterized. It accounts for less than 10% of all endometrial cancers and 80% of endometrial cancer-related deaths. Currently, staging surgery together with chemotherapy or radiotherapy, especially vaginal cuff brachytherapy, is the main treatment strategy for USC. Whole-exome sequencing combined with preclinical and clinical studies are verifying a series of effective and clinically accessible inhibitors targeting frequently altered genes, such as HER2 and PI3K3CA, in varying USC patient populations. Some progress has also been made in the immunotherapy field. The PD-1/PD-L1 pathway has been found to be activated in many USC patients, and clinical trials of PD-1 inhibitors in USC are underway. This review updates the progress of research regarding the molecular pathogenesis and putative clinical management of USC. Keywords: endometrial cancer; uterine serous carcinomaPrecis: Uterine serous cancer, although rare, is the most lethal type of uterine cancer. It has distinct molecular features and pathogenic pathways compared with other uterine cancer types Cancers 2020, 12, 686 2 of 21 heterogeneity, grade 3 EEC displays dissimilar features. Although a large number of grade 3 EEC cases show a serous-like phenotype, others display unequivocally endometrioid morphology [6,7]. Type II tumors are typically detected in women 70 years or older and carry a poor prognosis, high recurrence frequency, and much lower 5-year survival rate compared with type I tumors. In addition, type II tumors usually lack estrogen/progesterone receptors and do not respond to hormonal fluctuations [5].Among the type II tumors, uterine serous carcinoma (USC) is the most common subtype. This highly aggressive variant accounts for only 10% of all ECs but 80% of all EC-associated deaths [8,9]. The 5-year tumor-specific survival rate is 74% and 33% for early-and late-stage USC patients, respectively (and 89% and 77% for low-and high-grade EEC) [10]. Unlike type I EC, the risk of metastasis and recurrence of USC does not rely on primary tumor size or grade; this trait contributes to a low overall survival rate of 18% to 27%. Complete surgical staging is performed, comprising total hysterectomy, bilateral salpingo-oophorectomy, and lymph node dissection, followed by carboplatin and paclitaxel. In light of poor patient survival and high recurrence rates, the development of targeted therapies specific to USC pathway aberrations would aid in its management. However, conducting studies that focus solely on this rare subtype has been a constant challenge, making it difficult to determine optimal treatment strategies [9].

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“…These compounds are clinically used in hematologic malignancies and cutaneous T-cell lymphoma but are associated with high toxicity, poor selectivity and very little efficacy in solid tumors. To overcome those limitations, a second wave of epigenetic drugs targeting notably epigenetic writers, such as histone lysine methyltransferases, and epigenetic readers, like bromodomain and extraterminal motif (BET) family members, are currently in early phases of clinical development [1,2].…”

Section: You Beter Be Aware -Learnings From a Negative Phase 1 Study mentioning

confidence: 99%

“…Preclinical safety data did not indicate such risk -although pain is difficult to study in animals. Results from other BET inhibitor Phase 1 trials, in contrast, rather indicated hematopoietic and liver toxicity as well as nausea and fatigue as most common adverse events [1]. Also, our own experience from treating more than 240 patients with 15 different epigenetic drugs in Phase 1 trials rather pointed towards a late onset of toxicities [7], contrasting with the rapid appearance of pain symptoms as soon as the first dosing with the BET inhibitor BAY 1238097 [3].…”

Section: You Beter Be Aware -Learnings From a Negative Phase 1 Study mentioning

confidence: 99%

Untitled

2019

Oncotarget

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Targeting epigenetic modifications in cancer therapy: erasing the roadmap to cancer

Cited by 318 publications

References 207 publications

LncRNA LINRIS stabilizes IGF2BP2 and promotes the aerobic glycolysis in colorectal cancer

LncRNA LINRIS stabilizes IGF2BP2 and promotes the aerobic glycolysis in colorectal cancer

Pathogenesis and Clinical Management of Uterine Serous Carcinoma

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