I-BET726 suppresses human skin squamous cell carcinoma cell growth in vitro and in vivo

Liu, Zhengjun; Li, Ping; Yang, Yongqiang; Cai, Shang; Lin, Xiangwei; Chen, Min-Bin; Guo, Hailei

doi:10.1038/s41419-020-2515-z

Cited by 14 publications

(19 citation statements)

References 34 publications

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“…Whether miR-6784 exerted similar effects in other skin SCC cells was tested. The primary human skin SCC cells derived from two skin SCC patients (namely “C1/C2”, from Dr. Liu [ 14 , 27 ]), as well as SCC-9 established cells, were utilized. These cells were transfected with the lentivirus encoding pre-miR-6784 (lv-miR-6784).…”

Section: Resultsmentioning

confidence: 99%

“…Established skin SCC cell lines, A431 and SCC9, were provided by Dr. Liu at Wenzhou Medical University [ 14 , 27 ]. The primary skin SCC cells derived from two written-informed consent SCC patient (“C1/C2”, with PTEN depletion and p53-null) were provided by Dr. Liu [ 14 ] as well. Cells were cultured as reported before [ 39 ].…”

Section: Methodsmentioning

confidence: 99%

“…SphK1 inhibition, however, would lead to ceramide production that promotes cancer cell apoptosis [ 12 , 13 ]. The anti-skin SCC activity by I-BET726, a novel bromodomain-containing protein 4 (BRD4) inhibitor, has been associated with SphK1 inhibition and ceramide accumulation [ 14 ]. These results indicated that SphK1 inhibition or silencing should produce significant anti-skin SCC activity.…”

Section: Introductionmentioning

confidence: 99%

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SphK1-targeted miR-6784 inhibits functions of skin squamous cell carcinoma cells

Yao

et al. 2021

Aging

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Sphingosine kinase 1 (SphK1) is overexpressed in skin squamous cell carcinoma (SCC). It has emerged as a novel therapeutic oncotarget. The current study identified a novel SphK1-targeting microRNA, microRNA-6784 (miR-6784). Here, we show that miR-6784 is located at the cytoplasm of A431 skin SCC cells. It directly binds to SphK1 mRNA. Ectopic overexpression of miR-6784 inhibited SphK1 3’-untranslated region (UTR) luciferase activity and downregulated its expression. Moreover, miR-6784 overexpression caused ceramide accumulation in skin SCC cells. Functional studies in established (A431 and SCC9) and primary skin SCC cells revealed that miR-6784 overexpression inhibited cell viability, proliferation, migration, and invasion. It also simultaneously provoked apoptosis activation. Conversely, miR-6784 silencing by antagomiR-6784 induced SphK1 elevation and augmented A431 cell proliferation, migration, and invasion. miR-6784 overexpression-induced anti-A431 cell activity was inhibited by the expression of an UTR-null SphK1 construct. CRISPR/Cas9-induced SphK1 knockout inhibited A431 cell growth. Importantly, miR-6784 was completely ineffective when treating SphK1-knockout A431 cells. Collectively, miR-6784 silences SphK1 and inhibits skin SCC cell progression.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SphK1-targeted miR-6784 inhibits functions of skin squamous cell carcinoma cells

Yao

et al. 2021

Aging

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“…3a, b ). We then compared the anti-colon cancer cell activity of A1874 with other known BRD4-BET inhibitors, including JQ1 37 , 38 , CPI203 29 , 39 , and I-BET726 40 – 42 . In pCan1 cells and pCan2 cells, A1874-induced viability (CCK-8 OD) reduction (Fig.…”

Section: Resultsmentioning

confidence: 99%

The therapeutic effect of the BRD4-degrading PROTAC A1874 in human colon cancer cells

Qin

Jin

et al. 2020

Cell Death Dis

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A1874 is a novel BRD4-degrading proteolysis targeting chimera (PROTAC). In primary colon cancer cells and established HCT116 cells, A1874 potently inhibited cell viability, proliferation, cell cycle progression, as well as cell migration and invasion. The BRD4-degrading PROTAC was able to induce caspase and apoptosis activation in colon cancer cells. Furthermore, A1874-induced degradation of BRD4 protein and downregulated BRD-dependent genes (c-Myc, Bcl-2, and cyclin D1) in colon cancer cells. Significantly, A1874-induced anti-colon cancer cell activity was more potent than the known BRD4 inhibitors (JQ1, CPI203, and I-BET151). In BRD4-knockout colon cancer cells A1874 remained cytotoxic, indicating the existence of BRD4-independent mechanisms. In addition to BRD4 degradation, A1874 cytotoxicity in colon cancer cells was also associated with p53 protein stabilization and reactive oxygen species production. Importantly, the antioxidant N-acetyl-cysteine and the p53 inhibitor pifithrin-α attenuated A1874-induced cell death and apoptosis in colon cancer cells. In vivo, A1874 oral administration potently inhibited colon cancer xenograft growth in severe combined immuno-deficient mice. BRD4 degradation and p53 protein elevation, as well as apoptosis induction and oxidative stress were detected in A1874-treated colon cancer tissues. Together, A1874 inhibits colon cancer cell growth through both BRD4-dependent and -independent mechanisms.

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“…A constitutively-active Akt1 (ca-Akt1, S473D 22,31,32 ) was transduced to A549 cells. Stable A549 cells were established with FACS sorting and puromycin selection.…”

Section: Gdc-0349 Blocks Akt-mtor Activation In Nsclc Cellsmentioning

confidence: 99%

GDC-0349 inhibits non-small cell lung cancer cell growth

Han

Zhao

et al. 2020

Cell Death Dis

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Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related human mortality with a clear need for new therapeutic intervention. GDC-0349 is a potent and selective ATP-competitive mTOR inhibitor. In A549 cells and primary human NSCLC cells, GDC-0349 inhibited cell growth, proliferation, cell cycle progression, migration and invasion, while inducing significant apoptosis activation. Although GDC-0349 blocked Akt-mTORC1/2 activation in NSCLC cells, it also exerted cytotoxicity in Akt1-knockout A549 cells. Furthermore, restoring Akt-mTOR activation by a constitutively-active Akt1 only partially attenuated GDC-0349-induced A549 cell apoptosis, indicating the existence of Akt-mTOR-independent mechanisms. In NSCLC cells GDC-0349 induced sphingosine kinase 1 (SphK1) inhibition, ceramide accumulation, JNK activation and oxidative injury. Conversely, N-acetylcysteine, the JNK inhibitor and sphingosine 1-phosphate alleviated GDC-0349-induced NSCLC cell apoptosis. In vivo, daily oral administration of GDC-0349 potently inhibited NSCLC xenograft growth in mice. Akt-mTOR in-activation, SphK1 inhibition, JNK activation and oxidative stress were detected in NSCLC xenograft tissues with GDC-0349 administration. In summary, GDC-0349 inhibits NSCLC cell growth via Akt-mTOR-dependent and Akt-mTOR-independent mechanisms.

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I-BET726 suppresses human skin squamous cell carcinoma cell growth in vitro and in vivo

Cited by 14 publications

References 34 publications

SphK1-targeted miR-6784 inhibits functions of skin squamous cell carcinoma cells

SphK1-targeted miR-6784 inhibits functions of skin squamous cell carcinoma cells

The therapeutic effect of the BRD4-degrading PROTAC A1874 in human colon cancer cells

GDC-0349 inhibits non-small cell lung cancer cell growth

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