Downregulation of HMGA2 by the pan-deacetylase inhibitor panobinostat is dependent on hsa-let-7b expression in liver cancer cell lines

Fazio, Pietro Di; Montalbano, Roberta; Neureiter, Daniel; Alinger, Beate; Schmidt, Ansgar; Merkel, Anna Lena; Quint, Karl; Ocker, Matthias

doi:10.1016/j.yexcr.2012.04.018

Cited by 63 publications

(55 citation statements)

References 54 publications

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“…For example, Di Fazio et al (36) reported that let-7b exhibited an important tumor-suppressive role via inhibiting the expression of high-mobility group Figure 6. let-7f-5p decreases the luciferase activity of the 3'-UTRs of TP53, TP53INP1, TP53INP2 and caspase-3.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of let‑7f‑5p promotes chemotherapeutic resistance in colorectal cancer by directly repressing several pro‑apoptotic proteins

et al. 2018

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Abstract. Colorectal cancer (CRC) is one of the most frequently occurring primary malignant tumors worldwide. Chemotherapeutic resistance is a major clinical problem in the treatment of CRC. Therefore, it is of great importance to investigate novel biomarkers that may predict chemoresistance and facilitate the development of individualized treatment for patients with CRC. The present study reported that let-7f-5p expression was elevated in chemotherapy-resistant CRC tissues compared with chemotherapy-sensitive tissues. Furthermore, upregulating let-7f-5p increased the expression levels of the anti-apoptotic proteins, B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL), and decreased the activity of caspase-3 and caspase-9 in CRC cells. By contrast, downregulating let-7f-5p yielded the opposite effect. Notably, the results indicated that let-7f-5p promoted chemotherapeutic resistance by directly repressing the expression of several pro-apoptotic proteins, including tumor protein p53, tumor protein p53-inducible nuclear protein 1, tumor protein p53-inducible nuclear protein 2 and caspase-3. Therefore, a novel mechanism by which let-7f-5p enhances the resistance of CRC cells to chemotherapeutics has been revealed, indicating that silencing let-7f-5p may become an effective therapeutic strategy against CRC. IntroductionColorectal cancer (CRC) is one of the most prevalent causes of cancer-associated mortality worldwide (1,2). Clinically, 5-fluorouracil (5-FU)-based chemotherapy serves as the initial first-line chemotherapeutic drug of choice in patients with CRC; however, the response rates to 5-FU are ~15% in patients with advanced CRC (3). Although novel therapeutic approaches, including combination chemotherapy of 5-FU and oxaliplatin (FOLFOX) or irinotecan (FOLFIRI), have presented promising potential, the majority of the patients continue to exhibit inadequate responses (4,5). The failure of chemotherapy in CRC patients is primarily attributed to therapeutic resistance following a long period of treatment (6). These observations emphasize that chemotherapeutic resistance is a major obstacle in the treatment of CRC, and that the molecular mechanisms underlying this issue remain unclear.Chemotherapeutic resistance poses a major challenge in cancer chemotherapy. Chemoresistance of tumor cells develops primarily due to acquired resistance de novo, following an initially sensitive response, and/or in combination with pre-established cell-intrinsic mechanisms (7). A number of well-established mechanisms are reported to be involved in cancer drug resistance, including failure of the drug to reach or enter the target cell, formation of efflux pumps on the surface of tumor cells, increased expression of anti-apoptotic proteins, induction of drug-detoxifying mechanisms and upregulation of DNA repair enzymes (8,9). However, there is an absence of integral understanding of acquired drug resistance in the context of CRC. Such insight may be crucial for the

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Section: Discussionmentioning

confidence: 99%

Upregulation of let‑7f‑5p promotes chemotherapeutic resistance in colorectal cancer by directly repressing several pro‑apoptotic proteins

et al. 2018

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“…Because downregulation of MIRLET7B and subsequent upregulation of HMGA2 appear to be the direct results of the presence of an KMT2A fusion protein, correcting this deregulated MIRLET7B-HMGA2 pathway may also be an option. The pan-deacetylase inhibitor panobinostat activates MIRLET7B and downregulates HMGA2 (Di Fazio et al, 2012). Panobinostat may be another suitable drug because of its effectiveness and low toxicity and may exert beneficial effects when used in combination with the HMGA2 inhibitor.…”

Section: Discussionmentioning

confidence: 99%

HMGA2 as a potential molecular target inKMT2A-AFF1-positive infant acute lymphoblastic leukaemia

Eguchi‐Ishimae

Yagi

et al. 2015

Br J Haematol

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Acute lymphoblastic leukaemia (ALL) in infants is an intractable cancer in childhood. Although recent intensive chemotherapy progress has considerably improved ALL treatment outcome, disease cure is often accompanied by undesirable long-term side effects, and efficient, less toxic molecular targeting therapies have been anticipated. In infant ALL cells with KMT2A (MLL) fusion, the microRNA let-7b (MIRLET7B) is significantly downregulated by DNA hypermethylation of its promoter region. We show here that the expression of HMGA2, one of the oncogenes repressed by MIRLET7B, is reversely upregulated in infant ALL leukaemic cells, particularly in KMT2A-AFF1 (MLL-AF4) positive ALL. In addition to the suppression of MIRLET7B, KMT2A fusion proteins positively regulate the expression of HMGA2. HMGA2 is one of the negative regulators of CDKN2A gene, which encodes the cyclin-dependent kinase inhibitor p16INK4A . The HMGA2 inhibitor netropsin, when combined with demethylating agent 5-azacytidine, upregulated and sustained the expression of CDKN2A, which resulted in growth suppression of KMT2A-AFF1-expressing cell lines. This effect was more apparent compared to treatment with 5-azacytidine alone. These results indicate that the MIRLET7B-HMGA2-CDKN2A axis plays an important role in cell proliferation of leukaemic cells and could be a possible molecular target for the therapy of infant ALL with KMT2A-AFF1.

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“…Inhibitors of protein deacetylases represent a novel therapeutic option to infl uence HMGA2 expression. It was observed that Panobinostat strongly downregulated HMGA2 in HepG2 and Hep3B cells by transcriptional upregulation and promotion of the maturation of the tumor suppressor miRNA hsa-let-7b [ 77 ].…”

Section: Perspectivesmentioning

confidence: 99%

Genetic and Genomics of Uterine Myomas

Vergara

Greco

2014

Uterine Myoma, Myomectomy and Minimally Invasive Treatments

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Downregulation of HMGA2 by the pan-deacetylase inhibitor panobinostat is dependent on hsa-let-7b expression in liver cancer cell lines

Cited by 63 publications

References 54 publications

Upregulation of let‑7f‑5p promotes chemotherapeutic resistance in colorectal cancer by directly repressing several pro‑apoptotic proteins

Upregulation of let‑7f‑5p promotes chemotherapeutic resistance in colorectal cancer by directly repressing several pro‑apoptotic proteins

HMGA2 as a potential molecular target inKMT2A-AFF1-positive infant acute lymphoblastic leukaemia

Genetic and Genomics of Uterine Myomas

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