Targeting HMGA2 in Retinoblastoma Cells in vitro Using the Aptamer Strategy

Venkatesan, Narayanan; Deepa, Perinkulam Ravi; Raguraman, Rajeswari; Khetan, Vikas; Reddy, M. Ashwin; Krishnakumar, Subramanian

doi:10.1159/000447300

Cited by 10 publications

(8 citation statements)

References 33 publications

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“…We next investigated whether HMGA2 downmodulation would affect the chemosensitivity of RB cells. Consistent with a previous report [ 25 ], HMGA2 knockdown in RB cells increased the sensitivity to etoposide (Fig. 5a–c ).…”

Section: Resultssupporting

confidence: 93%

“…In this regard, HMGA2 was considered as the top candidate gene for a further investigation since inhibition of HMGA2 expression has been shown to reduce RB cell proliferation [ 21 , 28 ]. Moreover, HMGA2 is known to be involved in the DNA damage response and modulation of chemosensitivity in cancer cells in addition to its role in transcriptional regulation as a chromatin-associated protein [ 22 – 25 ]. When we monitored the expression changes of HMGA2 by EPZ5676 treatment, there was a gradual decrease at both transcript and protein levels over time (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…HMGA2 is a chromatin-associated protein which can modulate transcription by altering the chromatin structure and affinity of transcription factors, and ectopic expression of HMGA2 is known to induce neoplastic transformation and tumorigenesis [ 22 ]. Notably, HMGA2 is also involved in the modulation of DNA damage response by altering the expression or phosphorylation of DNA damage checkpoint proteins including ATM and ATR/CHK1 axis, leading to the increased sensitivity to diverse genotoxic insults upon HMGA2 downmodulation in cancer cells [ 23 – 25 ].…”

Section: Introductionmentioning

confidence: 99%

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Targeting of histone methyltransferase DOT1L plays a dual role in chemosensitization of retinoblastoma cells and enhances the efficacy of chemotherapy

Mao

Sun

et al. 2021

Cell Death Dis

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Aberrant and exclusive expression of chromatin regulators in retinoblastoma (RB) in contrast to terminally differentiated normal retina presents a unique opportunity of selective targeting for RB. However, precise roles of these chromatin regulators in RB development and their potential as therapeutic targets have not been defined thoroughly. Here, we report that targeting of disruptor of telomeric silencing 1-like (DOT1L), a histone H3K79 methyltransferase, sensitizes RB cells to chemotherapeutic drugs by impairing the DNA damage response and thereby potentiating apoptosis while it is largely inefficacious as a single-agent therapy. Moreover, we identified high mobility group AT-hook 2 (HMGA2) as a novel DOT1L target gene in RB cells and found that its aberrant expression is dependent on DOT1L. As HMGA2 depletion reduced CHK1 phosphorylation during DNA damage response and augmented the drug sensitivity in RB cells, our results suggested that DOT1L targeting has a dual role in chemosensitization of RB cells by directly interfering with the immediate involvement of DOT1L in early DNA damage response upon genotoxic insults and also by downregulating the expression of HMGA2 as a rather late effect of DOT1L inhibition. Furthermore, we provide the first preclinical evidence demonstrating that combined therapy with a DOT1L inhibitor significantly improves the therapeutic efficacy of etoposide in murine orthotopic xenografts of RB by rendering the response to etoposide more potent and stable. Taken together, these results support the therapeutic benefits of DOT1L targeting in combination with other chemotherapeutic agents in RB, with mechanistic insights into how DOT1L targeting can improve the current chemotherapy in an RB cell-selective manner.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting of histone methyltransferase DOT1L plays a dual role in chemosensitization of retinoblastoma cells and enhances the efficacy of chemotherapy

Mao

Sun

et al. 2021

Cell Death Dis

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“…17 Indeed, our previous studies revealed that targeting HMGA at the transcript as well as protein levels compromised RB survival in in vitro. 13,17 The selective delivery of either HMGA2 siRNA or HMGA aptamer to retinoblastoma can be achieved by targeting cell surface proteins those are overexpressed in RB cells. Previous studies have showed that nucleolin (NCL) is overexpressed on the surface of RB cells, and could be used for selective delivery of siRNA or aptamer.…”

mentioning

confidence: 98%

“… 16 In RB tumours, HMGA aptamer reduced cell proliferation by activation of TGFβ- SMAD4 -mediated apoptotic pathway and a synergistic effect was also observed with etoposide. 17 Indeed, our previous studies revealed that targeting HMGA at the transcript as well as protein levels compromised RB survival in in vitro . 13,17 The selective delivery of either HMGA2 siRNA or HMGA aptamer to retinoblastoma can be achieved by targeting cell surface proteins those are overexpressed in RB cells.…”

mentioning

confidence: 98%

Targeting HMGA protein inhibits retinoblastoma cell proliferation

et al. 2018

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Chromatin regulators in retinoblastoma: Biological roles and therapeutic applications

Lee

Kim

2020

Journal Cellular Physiology

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Retinoblastoma (RB) is a pediatric ocular tumor mostly occurring due to the biallelic loss of RB1 gene in the developing retina. Early studies of genomic aberrations in RB have provided a valuable insight into how RB can progress following the tumor‐initiating RB1 mutations and have established a notion that inactivation of RB1 gene is critical to initiate RB but this causative genetic lesion alone is not sufficient for malignant progression. With the advent of high‐throughput sequencing technologies, we now have access to the comprehensive genomic and epigenetic landscape of RB and have come to appreciate that RB tumorigenesis requires both genetic and epigenetic alterations that might be directly or indirectly driven by RB1 loss. This integrative perspective on RB tumorigenesis has inspired research efforts to better understand the types and functions of epigenetic mechanisms contributing to RB development, leading to the identification of multiple epigenetic regulators misregulated in RB in recent years. A complete understanding of the intricate network of genetic and epigenetic factors in modulation of gene expression during RB tumorigenesis remains a major challenge but would be crucial to translate these findings into therapeutic interventions. In this review, we will provide an overview of chromatin regulators identified to be misregulated in human RB among the numerous epigenetic factors implicated in RB development. For a subset of these chromatin regulators, recent findings on their functions in RB development and potential therapeutic applications are discussed.

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Targeting HMGA2 in Retinoblastoma Cells in vitro Using the Aptamer Strategy

Cited by 10 publications

References 33 publications

Targeting of histone methyltransferase DOT1L plays a dual role in chemosensitization of retinoblastoma cells and enhances the efficacy of chemotherapy

Targeting of histone methyltransferase DOT1L plays a dual role in chemosensitization of retinoblastoma cells and enhances the efficacy of chemotherapy

Targeting HMGA protein inhibits retinoblastoma cell proliferation

Chromatin regulators in retinoblastoma: Biological roles and therapeutic applications

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