2817 El Camino Real
Santa Clara CA 95051
Medical School: Other - 1983
Accepts Medicare: Yes
Participates In eRX: No
Participates In PQRS: No
Participates In EHR: No
License #: 7882T
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Genetic disruption of tubulin acetyltransferase, Î±TAT1, inhibits proliferation and invasion of colon cancer cells through decreases in Wnt1/Î²-catenin signaling. - Biochemical and biophysical research communications
Microtubules are required for diverse cellular processes, and abnormal regulation of microtubule dynamics is closely associated with severe diseases including malignant tumors. In this study, we report that Î±-tubulin N-acetyltransferase (Î±TAT1), a regulator of Î±-tubulin acetylation, is required for colon cancer proliferation and invasion via regulation of Wnt1 and its downstream genes expression. Public transcriptome analysis showed that expression of ATAT1 is specifically upregulated in colon cancer tissue. A knockout (KO) of ATAT1 in the HCT116 colon cancer cell line, using the CRISPR/Cas9 system showed profound inhibition of proliferative and invasive activities of these cancer cells. Overexpression of Î±TAT1 or the acetyl-mimic K40Q Î±-tubulin mutant in Î±TAT1 KO cells restored the invasiveness, indicating that microtubule acetylation induced by Î±TAT1 is critical for HCT116Â cell invasion. Analysis of colon cancer-related gene expression in Î±TAT1 KO cells revealed that the loss of Î±TAT1 decreased the expression of WNT1. Mechanistically, abrogation of tubulin acetylation by Î±TAT1 knockout inhibited localization of Î²-catenin to the plasma membrane and nucleus, thereby resulting in the downregulation of Wnt1 and of its downstream genes including CCND1, MMP-2, and MMP-9. These results suggest that Î±TAT1-mediated Wnt1 expression via microtubule acetylation is important for colon cancer progression.Copyright Â© 2016 Elsevier Inc. All rights reserved.
mDia1 regulates breast cancer invasion by controlling membrane type 1-matrix metalloproteinase localization. - Oncotarget
Mammalian diaphanous-related formin 1 (mDia1) expression has been linked with progression of malignant cancers in various tissues. However, the precise molecular mechanism underlying mDia1-mediated invasion in cancer cells has not been fully elucidated. In this study, we found that mDia1 is upregulated in invasive breast cancer cells. Knockdown of mDia1 in invasive breast cancer profoundly reduced invasive activity by controlling cellular localization of membrane type 1-matrix metalloproteinase (MT1-MMP) through interaction with microtubule tracks. Gene silencing and ectopic expression of the active form of mDia1 showed that mDia1 plays a key role in the intracellular trafficking of MT1-MMP to the plasma membrane through microtubules. We also demonstrated that highly invasive breast cancer cells possessed invasive activity in a 3D culture system, which was significantly reduced upon silencing mDia1 or MT1-MMP. Furthermore, mDia1-deficient cells cultured in 3D matrix showed impaired expression of the cancer stem cell marker genes, CD44 and CD133. Collectively, our findings suggest that regulation of cellular trafficking and microtubule-mediated localization of MT1-MMP by mDia1 is likely important in breast cancer invasion through the expression of cancer stem cell genes.
Extracellular Matrix Rigidity-dependent Sphingosine-1-phosphate Secretion Regulates Metastatic Cancer Cell Invasion and Adhesion. - Scientific reports
Dynamic interaction between cancer cells and the surrounding microenvironment is critical for cancer progression via changes in cellular behavior including alteration of secreted molecules. However, the molecular mechanisms underlying the influence exerted by the cancer microenvironment on secretion of molecules during cancer progression remain largely unknown. In this study, we report that secretion of spingsine-1-phosphate (S1P) and its regulator, SphK1 expression is dependent of the substrate rigidity, which is critical for the balance between cancer cell invasion and adhesion. Conditioned media (CM) of MDA-MB-231, an aggressive breast cancer cell obtained from soft substrate (~0.5â€‰kPa) induced chemo-attractive invasion, while CM obtained from stiff substrate (~2.5â€‰kPa) increased cell adhesion instead. We found that the expression of SphK1 is upregulated in the stiff substrate, resulting in an increase in S1P levels in the CM. We also found that upregulation of SphK1 expression in the stiff substrate is dominant in metastatic cancer cells but not in primary cancer cells. These results suggest that alterations in the mechanical environment of the ECM surrounding the tumor cells actively regulate cellular properties such as secretion, which in turn, may contribute to cancer progression.
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2817 El Camino Real Santa Clara, CA 95051
3655 Pruneridge Ave Apt 224