Karyopherin-β1 Regulates Radioresistance and Radiation-Increased Programmed Death-Ligand 1 Expression in Human Head and Neck Squamous Cell Carcinoma Cell Lines

Hazawa, Masaharu; Yoshino, Hironori; Nakagawa, Yuta; Shimizume, Reina; Nitta, Keisuke; Sato, Yoshiaki; Sato, Mariko; Wong, Richard W.; Kashiwakura, Ikuo

doi:10.3390/cancers12040908

Cited by 10 publications

(7 citation statements)

References 47 publications

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“…We next elucidated the functions of ACP-1n against cancer growth [13,35,39,40] and its functional significance in the maintenance of CRC in vitro by targeting BRD4 and BRD4driven gene expression in colorectal cancer HCT116 cells. Consistent with the previous results from an in vitro droplet formation assay (Figure 1C), immunofluorescent confocal imaging of BRD4 proteins demonstrated that the numbers of BRD4 puncta (representing BRD4 assembly) significantly decreased following ACP-1n treatment (Figure 2A,B).…”

Section: Aminocyclopropenone Compound Acp-1n Prevented Super-enhancer-driven Myc Expression By Blocking Brd4 Assembly In the Nucleusmentioning

confidence: 99%

Discovery of a Novel Aminocyclopropenone Compound That Inhibits BRD4-Driven Nucleoporin NUP210 Expression and Attenuates Colorectal Cancer Growth

Kondo

Mishiro

Iwashima

et al. 2022

Cells

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Epigenetic deregulation plays an essential role in colorectal cancer progression. Bromodomains are epigenetic “readers” of histone acetylation. Bromodomain-containing protein 4 (BRD4) plays a pivotal role in transcriptional regulation and is a feasible drug target in cancer cells. Disease-specific elevation of nucleoporin, a component of the nuclear pore complex (NPC), is a determinant of cancer malignancy, but BRD4-driven changes of NPC composition remain poorly understood. Here, we developed novel aminocyclopropenones and investigated their biological effects on cancer cell growth and BRD4 functions. Among 21 compounds developed here, we identified aminocyclopropenone 1n (ACP-1n) with the strongest inhibitory effects on the growth of the cancer cell line HCT116. ACP-1n blocked BRD4 functions by preventing its phase separation ability both in vitro and in vivo, attenuating the expression levels of BRD4-driven MYC. Notably, ACP-1n significantly reduced the nuclear size with concomitant suppression of the level of the NPC protein nucleoporin NUP210. Furthermore, NUP210 is in a BRD4-dependent manner and silencing of NUP210 was sufficient to decrease nucleus size and cellular growth. In conclusion, our findings highlighted an aminocyclopropenone compound as a novel therapeutic drug blocking BRD4 assembly, thereby preventing BRD4-driven oncogenic functions in cancer cells. This study facilitates the development of the next generation of effective and potent inhibitors of epigenetic bromodomains and extra-terminal (BET) protein family.

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Section: Aminocyclopropenone Compound Acp-1n Prevented Super-enhancer-driven Myc Expression By Blocking Brd4 Assembly In the Nucleusmentioning

confidence: 99%

Discovery of a Novel Aminocyclopropenone Compound That Inhibits BRD4-Driven Nucleoporin NUP210 Expression and Attenuates Colorectal Cancer Growth

Kondo

Mishiro

Iwashima

et al. 2022

Cells

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“…Hazawa et al. [ 37 ] demonstrated that importazole (an inhibitor of KPNB1 ) increased the expression level of p53‐upregulated modulator of apoptosis ( PUMA ) and decreased the expression level of nucleoporin 62 ( NUP62 ) by attenuating ΔNp63α nuclear import, which ultimately enhanced apoptosis in SCC cells. However, it was not clarified whether ΔNp63α ‐mediated nuclear transport is involved the regulation of ncRNAs in the OSCC process.…”

Section: Overview On Oscc and Chemoresistancementioning

confidence: 99%

The role of non‐coding RNAs in drug resistance of oral squamous cell carcinoma and therapeutic potential

Meng¹,

Lou

Yang³

et al. 2021

Cancer Communications

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Oral squamous cell carcinoma (OSCC), the eighth most prevalent cancer in the world, arises from the interaction of multiple factors including tobacco, alcohol consumption, and betel quid. Chemotherapeutic agents such as cisplatin, 5‐fluorouracil, and paclitaxel have now become the first‐line options for OSCC patients. Nevertheless, most OSCC patients eventually acquire drug resistance, leading to poor prognosis. With the discovery and identification of non‐coding RNAs (ncRNAs), the functions of dysregulated ncRNAs in OSCC development and drug resistance are gradually being widely recognized. The mechanisms of drug resistance of OSCC are intricate and involve drug efflux, epithelial‐mesenchymal transition, DNA damage repair, and autophagy. At present, strategies to explore the reversal of drug resistance of OSCC need to be urgently developed. Nano‐delivery and self‐cellular drug delivery platforms are considered as effective strategies to overcome drug resistance due to their tumor targeting, controlled release, and consistent pharmacokinetic profiles. In particular, the combined application of new technologies (including CRISPR systems) opened up new horizons for the treatment of drug resistance of OSCC. Hence, this review explored emerging regulatory functions of ncRNAs in drug resistance of OSCC, elucidated multiple ncRNA‐meditated mechanisms of drug resistance of OSCC, and discussed the potential value of drug delivery platforms using nanoparticles and self‐cells as carriers in drug resistance of OSCC.

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“…We previously reported that KPNB1 inhibition increases cytotoxicity in various cancer cells, including HNSCC cells. It also increases radiosensitivity and enhances radiation-induced apoptosis specifically in HNSCC cells [ 10 ], suggesting that KPNB1 can transport nucleoproteins that specifically regulate radioresistance in HNSCC cells.…”

Section: Introductionmentioning

confidence: 99%

ΔNp63 Regulates Radioresistance in Human Head and Neck Squamous Carcinoma Cells

Sato,

Yoshino,

Sato

et al. 2023

CIMB

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Radiation therapy is commonly used to treat head and neck squamous cell carcinoma (HNSCC); however, recurrence results from the development of radioresistant cancer cells. Therefore, it is necessary to identify the underlying mechanisms of radioresistance in HNSCC. Previously, we showed that the inhibition of karyopherin-β1 (KPNB1), a factor in the nuclear transport system, enhances radiation-induced cytotoxicity, specifically in HNSCC cells, and decreases the localization of SCC-specific transcription factor ΔNp63. This suggests that ΔNp63 may be a KPNB1-carrying nucleoprotein that regulates radioresistance in HNSCC. Here, we determined whether ΔNp63 is involved in the radioresistance of HNSCC cells. Cell survival was measured by a colony formation assay. Apoptosis was assessed by annexin V staining and cleaved caspase-3 expression. The results indicate that ΔNp63 knockdown decreased the survival of irradiated HNSCC cells, increased radiation-induced annexin V+ cells, and cleaved caspase-3 expression. These results show that ΔNp63 is involved in the radioresistance of HNSCC cells. We further investigated which specific karyopherin-α (KPNA) molecules, partners of KPNB1 for nuclear transport, are involved in nuclear ΔNp63 expression. The analysis of nuclear ΔNp63 protein expression suggests that KPNA1 is involved in nuclear ΔNp63 expression. Taken together, our results suggest that ΔNp63 is a KPNB1-carrying nucleoprotein that regulates radioresistance in HNSCC.

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Karyopherin-β1 Regulates Radioresistance and Radiation-Increased Programmed Death-Ligand 1 Expression in Human Head and Neck Squamous Cell Carcinoma Cell Lines

Cited by 10 publications

References 47 publications

Discovery of a Novel Aminocyclopropenone Compound That Inhibits BRD4-Driven Nucleoporin NUP210 Expression and Attenuates Colorectal Cancer Growth

Discovery of a Novel Aminocyclopropenone Compound That Inhibits BRD4-Driven Nucleoporin NUP210 Expression and Attenuates Colorectal Cancer Growth

The role of non‐coding RNAs in drug resistance of oral squamous cell carcinoma and therapeutic potential

ΔNp63 Regulates Radioresistance in Human Head and Neck Squamous Carcinoma Cells

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