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Cross-talk between YAP and RAR-RXR Drives Expression of Stemness Genes to Promote 5-FU Resistance and Self-Renewal in Colorectal Cancer Cells.
- Source :
-
Molecular cancer research : MCR [Mol Cancer Res] 2021 Apr; Vol. 19 (4), pp. 612-622. Date of Electronic Publication: 2021 Jan 20. - Publication Year :
- 2021
-
Abstract
- The mechanisms whereby the Hippo pathway effector YAP regulates cancer cell stemness, plasticity, and chemoresistance are not fully understood. We previously showed that in 5-fluorouracil (5-FU)-resistant colorectal cancer cells, the transcriptional coactivator YAP is differentially regulated at critical transitions connected with reversible quiescence/dormancy to promote metastasis. Here, we found that experimental YAP activation in 5-FU-sensitive and 5-FU-resistant HT29 colorectal cancer cells enhanced nuclear YAP localization and the transcript levels of the retinoic acid (RA) receptors RARα/γ and RAR target genes CYP26A1, ALDH1A3 , and LGR5 through RA Response Elements (RARE). In these two cell models, constitutive YAP activation reinforced the expression of the stemness biomarkers and regulators ALDH1A3, LGR5, and OCT4. Conversely, YAP silencing, RAR/RXR inhibition by the pan-RAR antagonist BMS493, and vitamin A depletion downregulated stemness traits and self-renewal. Regarding the mechanisms engaged, proximity-dependent labeling, nuclear YAP pulldown coupled with mass spectrometry, and chromatin immunoprecipitation (ChIP)/re-ChIP experiments revealed: (i) the nuclear colocalization/interaction of YAP with RARγ and RXRs; and (ii) combined genomic co-occupancy of YAP, RARα/γ, and RXRα interactomes at proximal RAREs of LGR5 and ALDH1A3 promoters. Moreover, activation of the YAP/RAR-RXR cross-talk in colorectal cancer cells promoted RAR self-activation loops via vitamin A metabolism, RA, and active RAR ligands generated by ALDH1A3. Together, our data identify YAP as a bona fide RAR-RXR transcriptional coactivator that acts through RARE-activated stemness genes. IMPLICATIONS: Targeting the newly identified YAP/RAR-RXR cross-talk implicated in cancer cell stemness maintenance may lead to multitarget combination therapies for patients with colorectal cancer.<br /> (©2021 American Association for Cancer Research.)
- Subjects :
- Cell Line, Tumor
Cell Self Renewal physiology
Colorectal Neoplasms genetics
Colorectal Neoplasms pathology
Drug Resistance, Neoplasm
HT29 Cells
Humans
Neoplastic Stem Cells drug effects
Neoplastic Stem Cells pathology
Receptor Cross-Talk
Up-Regulation
Cell Cycle Proteins metabolism
Colorectal Neoplasms drug therapy
Colorectal Neoplasms metabolism
Fluorouracil pharmacology
Neoplastic Stem Cells metabolism
Receptors, Retinoic Acid metabolism
Retinoid X Receptors metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3125
- Volume :
- 19
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular cancer research : MCR
- Publication Type :
- Academic Journal
- Accession number :
- 33472949
- Full Text :
- https://doi.org/10.1158/1541-7786.MCR-20-0462