|
| Status |
Public on May 23, 2023 |
| Title |
ACK1/TNK2 Epigenetically Regulates Cell Cycle Program to Promote Breast Cancer Resistance to CDK4/6 inhibitor (RNA-Seq) |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Over-activation of oncogenes by aberrant expression of epigenetic modulators, overcoming cell cycle checkpoints and bestowing infinite multiplication potency acts as the mainstay of malignancy. We identified one such non-receptor tyrosine kinase ACK1 as an epigenetic regulator of cell cycle genes governing the G2/M transition of breast cancer cells. ACK1 was found to be over-activated (pY264-ACK1) in most of the breast cancer sub-types, independent of their hormone receptor status, as assessed by the Tissue-microarray analysis of nearly 400 breast cancer patient samples. ACK1 primed the epigenetic landscape surrounding the genes CCNB1, CCNB2 and CDC20 by depositing Y88-H4 histone activation marks, in turn initiating their efficient transcription. Pharmacological inhibition of ACK1 using small molecular inhibitor (R)-9b not only reversed this transcriptional potential but also sensitized the cells to a G2/M arrest, culminating in breast cancer cell death and tumor regression in in vivo xenograft models of breast cancer. Further, ACK1 was also found to modulate expression of the gene CXCR4, circumventing breast cancer metastasis on ACK1 ablation. In addition, ACK1 inhibition was also found to counteract the resistance of RB1 deficient breast cancer cells to the CDK4/6 inhibitor palbociclib, overcoming road blocks to conventional therapeutics. Overall, our data warrants the identification of ACK1 as an epigenetic controller of genes essential for the successful establishment and progression of breast cancer and signifies development of therapeutics against ACK1 to combat intrinsic and acquired breast cancer resistance.
|
| |
|
| Overall design |
MDA-MB-453 and HCC-1395 breast cancer cells were treated overnight with 5µM (R)-9b (also known as dz67) and RNA was prepared from these cells.
|
| |
|
| Contributor(s) |
Mahajan N |
| Citation(s) |
37330596 |
| |
| Submission date |
May 17, 2022 |
| Last update date |
Sep 12, 2023 |
| Contact name |
Tiandao Li |
| Organization name |
Washington University
|
| Street address |
4444 Forest Park Ave
|
| City |
St Louis |
| State/province |
MO |
| ZIP/Postal code |
63108 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
|
| Samples (4)
|
|
| This SubSeries is part of SuperSeries: |
| GSE203232 |
ACK1/TNK2 Epigenetically Regulates Cell Cycle Program to Promote Breast Cancer Resistance to CDK4/6 inhibitor |
|
| Relations |
| BioProject |
PRJNA839097 |
Less...
More...