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| Status |
Public on Oct 30, 2023 |
| Title |
HOXC6 drives a therapeutically targetable pancreatic cancer growth and metastasis pathway via stimulating MSK1 kinase and suppressing PPP2R2B protein |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, which lacks effective therapies. Here, we demonstrate that the transcription factor, HOXC6, is overexpressed in most PDACs, and its inhibition blocks PDAC tumor growth and metastasis. HOXC6 transcriptionally activates tumor-promoting kinase MSK1 and suppresses tumor-inhibitory protein PPP2R2B in PDAC. HOXC6-induced PPP2R2B suppression causes mTOR pathway activation, which facilitates PDAC growth. Also, MSK1 upregulation by HOXC6 is necessary for PDAC growth due to its ability to suppress apoptosis via its substrate DDX17. Combinatorial pharmacological inhibition of MSK1 and mTOR potently suppressed PDAC tumor growth and metastasis in PDAC mouse models. PDAC cells with acquired resistance to MSK1/mTOR-inhibitors displayed activated IGF1R signaling and were successfully eradicated by IGF1R inhibitor. Furthermore, MEK inhibitor trametinib enhanced the efficacy of dual MSK1 and mTOR inhibition. Collectively, these results identify therapeutic vulnerabilities of PDAC and an approach to overcome acquired drug resistance to prolong therapeutic benefit.
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| Overall design |
AsPC1 cells stably expressing two individual shRNAs against MSK1 were used to prepare the total RNA, followed by RiboRNA depletion with random priming and RNASeq Illumina Hi-Seq 2500 platform, with three biological replicates for each sample.
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| Contributor(s) |
Gupta R, Wajapeyee N, Malvi P |
| Citation(s) |
37951219 |
| Submission date |
May 10, 2020 |
| Last update date |
Dec 14, 2023 |
| Contact name |
Narendra Wajapeyee |
| E-mail(s) |
nwajapey@uab.edu
|
| Phone |
205-934-5331
|
| Organization name |
University of Alabama at Birmingham
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| Department |
Department of Biochemistry and Molecular Genetics
|
| Street address |
720 20th Street South, Kaul 540A
|
| City |
Birmingham |
| State/province |
AL |
| ZIP/Postal code |
35233 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (9)
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| This SubSeries is part of SuperSeries: |
| GSE150225 |
The role of MSK1 in pancreatic adenocarcinoma (PDAC) progression |
|
| Relations |
| BioProject |
PRJNA631536 |
| SRA |
SRP260988 |
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