RIP140 regulates transcription factor HES1 oscillatory expression and mitogenic activity in colon cancer cells
Nour Sfeir1,2,3,4, Marilyn Kajdan1,2,3,4, Stéphan Jalaguier1,2,3,4
1IRCM, Institut de Recherche en Cancérologie de Montpellier, France.
Abstract:
The transcription factor receptor-interacting protein 140 (RIP140) regulates intestinal homeostasis and tumorigenesis through Wnt signaling. In this study, we investigated its effect on the Notch/HES1 signaling pathway. In colorectal cancer (CRC) cell lines, RIP140 positively regulated HES1 gene expression at the transcriptional level via a recombining binding protein suppressor of hairless (RBPJ)/neurogenic locus notch homolog protein 1 (NICD)-mediated mechanism. In support of these in vitro data, RIP140 and HES1 expression significantly correlated in mouse intestine and in a cohort of CRC samples, thus supporting the positive regulation of HES1 gene expression by RIP140. Interestingly, when the Notch pathway is fully activated, RIP140 exerted a strong inhibition of HES1 gene transcription controlled by the level of HES1 itself. Moreover, RIP140 directly interacts with HES1 and reversed its mitogenic activity in human CRC cells. In line with this observation, HES1 levels were associated with a better patient survival only when tumors expressed high levels of RIP140. Our data identify RIP140 as a key regulator of the Notch/HES1 signaling pathway, with a dual effect on HES1 gene expression at the transcriptional level and a strong impact on colon cancer cell proliferation.
Insights
Receptor-interacting protein 140 (RIP140) influences colorectal cancer by regulating the Notch/HES1 pathway. It impacts HES1 expression and colon cancer cell proliferation, affecting patient survival.
Area of Science:
- Molecular Biology
- Oncology
- Cell Signaling
Background:
- Receptor-interacting protein 140 (RIP140) is known to regulate intestinal homeostasis and tumorigenesis via Wnt signaling.
- The Notch signaling pathway plays a critical role in various cellular processes, including cancer development.
Purpose of the Study:
- To investigate the role of RIP140 in the Notch/HES1 signaling pathway.
- To elucidate the mechanism by which RIP140 affects HES1 gene expression and colorectal cancer (CRC) cell proliferation.
Main Methods:
- In vitro studies using CRC cell lines to assess RIP140's effect on HES1 gene expression.
- Analysis of RIP140 and HES1 expression correlation in mouse intestine and human CRC samples.
- Investigation of RIP140's interaction with HES1 and its impact on mitogenic activity and patient survival.
Main Results:
- RIP140 positively regulates HES1 gene expression transcriptionally through a RBPJ/NICD-mediated mechanism in CRC cells.
- RIP140 and HES1 expression are significantly correlated in mouse and human CRC tissues.
- RIP140 directly interacts with HES1, inhibiting its mitogenic activity and influencing patient survival in CRC.
- RIP140 exhibits a dual effect on HES1 transcription, inhibiting it when the Notch pathway is highly activated.
Conclusions:
- RIP140 is a key regulator of the Notch/HES1 signaling pathway in colorectal cancer.
- RIP140 modulates HES1 gene expression and colon cancer cell proliferation, impacting patient outcomes.
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