Identification of temozolomide resistance factors in glioblastoma via integrative miRNA/mRNA regulatory network analysis

Hiddingh, Lotte; Raktoe, Rajiv S.; Jeuken, Judith; Hulleman, Esther; Noske, David P.; Kaspers, Gertjan J. L.; Vandertop, W. Peter; Wesseling, Pieter; Würdinger, Thomas

doi:10.1038/srep05260

Cited by 33 publications

(30 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TMZ is a classical chemotherapy drug for glioma, which is normally used by patients with GBM followed by surgical resection and radiotherapy (24). However, the majority of patients with glioma develop resistance to TMZ during treatment (25). Thus, it was hypothesized that glioma may use or develop 'DNA repairing' and 'toxin pumping-out' strategies to remain resistant.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of SALL4 expression using RNA interference induces cell cycle arrest, enhances early apoptosis, inhibits invasion and increases chemosensitivity to temozolomide in U251 glioma cells

et al. 2017

View full text Add to dashboard Cite

Abstract. Spalt-like transcription factor 4 (SALL4) is essential for the maintenance of the self-renewal and pluripotent properties in embryonic stem cells. Although the detailed mechanism remains unclear, dysregulation of SALL4 has been detected in various malignancies. Previously, the authors' of the present study reported that the expression level of SALL4 was associated with the poor prognosis of glioblastoma multiforme (GBM). The present study aimed to investigate the function of SALL4 in U251 human glioblastoma cells, including apoptosis and invasion inhibition. It was revealed that knockdown of SALL4 expression through RNA interference induced cell cycle arrest, enhanced early apoptosis and significantly inhibited invasion. Furthermore, downregulation of SALL4 was associated with a significantly lower expression level of the core transcription factors, including POU class 5 homeobox 1, SRY-box 2 and Nanog homeobox. In addition, inhibition of SALL4 significantly reduced the concentration of chemotherapeutic agent temozolomide required to inhibit cell growth by 50%, which decreased from 113.66±23.07 and 114.93±20.91 µg/ml to 68.34±3.52 and 67.44±4.71 µg/ml in two independent short interfering RNA transfected groups. These results indicate that SALL4 serves an important role in the GBM pathophysiology and targeting SALL4 may be a potential approach to the treatment of GBM. IntroductionGlioma is the most common subgroup type of brain tumor, with an incidence of 5-6/100,000 cases/year in the United States (1). Among all types of glioma, glioblastoma multiforme (GBM) accounts for ~50% of cases and has the most malignant phenotype (2). Despite the extensive developments that have been invested in surgical techniques and therapeutic agents, 88% of patients with GBM succumb to this disease within 3 years (3). GBM remains one of the most challenging malignancies worldwide.Embryonic stem cells (ESCs) are known for their potent pluripotency and are able to differentiate into >220 cell types in the adult body. The human homologue of the drosophila spalt-like transcription factor 4 (SALL4) is a zinc-finger transcription factor, which is responsible for maintaining pluripotency and longevity of ESCs (4-6). Previously, cancer stem cells (CSCs) have been identified in various types of malignancies (7,8) and demonstrate high self-renewal capabilities able to sustain tumor growth (9). Thus far, ESCs and CSCs have been revealed to share numerous biological similarities with the SALL4 expression pattern being one of them. In various types of tumors, high SALL4 expression level has been associated with increased malignancy, including increased metastasis, enhanced proliferation (10-12) and poor differentiation (13,14).In the authors' previous study, it was demonstrated that SALL4 was highly expressed in glioma and significantly associated with poor survival (15). The present study further investigated the biological role of SALL4 in the tumorigenesis of glioma and explored the underlying mechanism of action. It was revealed th...

show abstract

Section: Discussionmentioning

confidence: 99%

Knockdown of SALL4 expression using RNA interference induces cell cycle arrest, enhances early apoptosis, inhibits invasion and increases chemosensitivity to temozolomide in U251 glioma cells

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The accumulation of BRD2 was confirmed by live cell imaging of YFP-BRD2, which showed that BRD2 accumulates as fast as NBS1 to damaged DNA at laserstripes, but with a shorter retention time at DNA lesions as compared to that of NBS1 ( Fig EV2C). PHF6 was also recently identified as a potential sensitizing factor for drug treatment in resistant glioblastoma [45], which indicates that this protein is important for development and tumorigenesis. Interestingly, another hit from our screen, the transcriptional regulator PHF6 (PHD finger 6), was found to be mutated in Börjeson-Forssman-Lehmann syndrome, which is a rare X-linked genetic disorder characterized by mental retardation, craniopharyngeal abnormalities, and hematological cancers [39][40][41][42][43][44].…”

mentioning

confidence: 98%

PHF6 promotes non‐homologous end joining and G2 checkpoint recovery

et al. 2019

View full text Add to dashboard Cite

The cellular response to DNA breaks is influenced by chromatin compaction. To identify chromatin regulators involved in the DNA damage response, we screened for genes that affect recovery following DNA damage using an RNAi library of chromatin regulators. We identified genes involved in chromatin remodeling, sister chromatid cohesion, and histone acetylation not previously associated with checkpoint recovery. Among these is the PHD finger protein 6 (PHF6), a gene mutated in Börjeson-Forssman-Lehmann syndrome and leukemic cancers. We find that loss of PHF6 dramatically compromises checkpoint recovery in G2 phase cells. Moreover, PHF6 is rapidly recruited to sites of DNA lesions in a PARPdependent manner and required for efficient DNA repair through classical non-homologous end joining. These results indicate that PHF6 is a novel DNA damage response regulator that promotes end joining-mediated repair, thereby stimulating timely recovery from the G2 checkpoint.

show abstract

“…Some chemotherapy can regulate miRNA to modulate tumor growth, such as integrative miRNA/mRNA regulatory network mediates temozolomide resistance in glioblastoma [73]. Some reports advocate nutritional intervention as part of the “watch-and-wait” approach, because diverse dietary bioactive components, e.g., butyrate, folate, retinoids, curcumin, do exert their biological or clinical effects [74], in part, through modulation of miRNA expression [75].…”

Section: Clinical Relevance and Implicationsmentioning

confidence: 99%

Tissue Elasticity Bridges Cancer Stem Cells to the Tumor Microenvironment Through microRNAs: Implications for a ″Watch-and-Wait″� Approach to Cancer

Luo

et al. 2017

CSCR

View full text Add to dashboard Cite

Targeting the tumor microenvironment (TME) through which cancer stem cells (CSCs) crosstalk for cancer initiation and progression, may open up new treatments different from those centered on the original hallmarks of cancer genetics thereby implying a new approach for suppression of TME-driven activation of CSCs. Cancer is dynamic, heterogeneous, evolving with the TME and can be influenced by tissue-specific elasticity. One of the mediators and modulators of the crosstalk between CSCs and mechanical forces is miRNA, which can be developmentally regulated, in a tissue- and cell-specific manner. Here, based on our previous data, we provide a framework through which such gene expression changes in response to external mechanical forces can be understood during cancer progression. Recognizing the ways mechanical forces regulate and affect intracellular signals with applications in cancer stem cell biology. Such TME-targeted pathways shed new light on strategies for attacking cancer stem cells with fewer side effects than traditional gene-based treatments for cancer, requiring a “watch-and-wait” approach. We attempt to address both normal brain microenvironment and tumor microenvironment as both works together, intertwining in pathology and physiology – a balance that needs to be maintained for the “watch-and-wait” approach to cancer. Thus, this review connected the subjects of tissue elasticity, tumor microenvironment, epigenetic of miRNAs, and stem-cell biology that are very relevant in cancer research and therapy. It attempts to unify apparently separate entities in a complex biological web, network, and system in a realistic and practical manner, i.e., to bridge basic research with clinical application.

show abstract

Identification of temozolomide resistance factors in glioblastoma via integrative miRNA/mRNA regulatory network analysis

Cited by 33 publications

References 51 publications

Knockdown of SALL4 expression using RNA interference induces cell cycle arrest, enhances early apoptosis, inhibits invasion and increases chemosensitivity to temozolomide in U251 glioma cells

Knockdown of SALL4 expression using RNA interference induces cell cycle arrest, enhances early apoptosis, inhibits invasion and increases chemosensitivity to temozolomide in U251 glioma cells

PHF6 promotes non‐homologous end joining and G2 checkpoint recovery

Tissue Elasticity Bridges Cancer Stem Cells to the Tumor Microenvironment Through microRNAs: Implications for a ″Watch-and-Wait″� Approach to Cancer

Contact Info

Product

Resources

About