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Wnt/β-catenin signaling and p68 conjointly regulate CHIP in colorectal cancer

Satadeepa Kal, Shrabastee Chakraborty, Subhajit Karmakar, Mrinal K Ghosh
doi: https://doi.org/10.1101/2021.06.20.449107
Satadeepa Kal
Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector–V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India
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Shrabastee Chakraborty
Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector–V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India
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Subhajit Karmakar
Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector–V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India
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Mrinal K Ghosh
Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector–V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India
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  • For correspondence: mrinalghosh@iicb.res.in mrinal.res@gmail.com
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Abstract

The differential expression pattern of Carboxy terminus of Hsc70 Interacting Protein (CHIP, alias STIP1 Homology and U–box Containing Protein 1 or STUB1) in cancers is associated with ubiquitination mediated degradation of its client proteins. Emerging evidences suggest its abundant expression of CHIP in colorectal cancer compared to normal tissues, but the mechanistic detail of this augmented expression pattern is unclear. The signature driver of canonical Wnt pathway, β-catenin, and its co-activator RNA helicase p68, are also overexpressed in colorectal cancer. In this study, we describe a novel mechanism of Wnt/β-catenin and p68 mediated transcriptional activation of CHIP gene leading to enhanced proliferation of colorectal cancer cells. Wnt3A treatment and pharmacological activation of canonical Wnt signaling pathway resulted in increased nuclear translocation of β-catenin and elevated expression of CHIP. Likewise, overexpression and knockdown of β-catenin and p68 upregulated and downregulated CHIP expression, respectively, at both mRNA and protein levels. After cloning CHIP promoter, the increased and decreased promoter activities of CHIP induced by overexpression and knockdown of either β-catenin or p68 further confirmed transcriptional regulation of CHIP gene by Wnt/β-catenin signaling cascade. p68 along with β-catenin were found to occupy Transcription Factor 4 (TCF4) binding sites on endogenous CHIP promoter and regulate its transcription. Finally, enhanced cellular propagation and migration of colorectal cancer cells induced by ‘Wnt/β-catenin-p68–CHIP’ axis established the significance of this pathway in oncogenesis. To the best of our knowledge, this is the first report elucidating the mechanistic details of transcriptional regulation of CHIP (STUB1) gene expression.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Footnotes: CHIP: Carboxy terminus of Hsc70 Interacting Protein; STUB1: STIP1 Homology and U–box Containing Protein 1; TCF4: Transcription Factor 4; LiCl: Lithium Chloride; GAPDH: Glyceraldehyde 3-Phosphate Dehydrogenase

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Posted June 20, 2021.
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Wnt/β-catenin signaling and p68 conjointly regulate CHIP in colorectal cancer
Satadeepa Kal, Shrabastee Chakraborty, Subhajit Karmakar, Mrinal K Ghosh
bioRxiv 2021.06.20.449107; doi: https://doi.org/10.1101/2021.06.20.449107
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Wnt/β-catenin signaling and p68 conjointly regulate CHIP in colorectal cancer
Satadeepa Kal, Shrabastee Chakraborty, Subhajit Karmakar, Mrinal K Ghosh
bioRxiv 2021.06.20.449107; doi: https://doi.org/10.1101/2021.06.20.449107

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