14‐3‐3σ restricts YY1 to the cytoplasm, promoting therapy resistance, and tumor progression in colorectal cancer

Author:

Lonare Amol12,Raychaudhuri Kumarkrishna12,Shah Sanket23,Madhu Gifty1,Sachdeva Anoushka1,Basu Sneha1,Thorat Rahul4,Gupta Sanjay23,Dalal Sorab N.12ORCID

Affiliation:

1. Cell and Tumour Biology, Advanced Centre for Treatment Research and Education in Cancer (ACTREC) Tata Memorial Centre Navi Mumbai India

2. Homi Bhabha National Institute, Training School Complex Mumbai India

3. Epigenetics and Chromatin Biology Group, Gupta Lab, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre Navi Mumbai India

4. Laboratory Animal Facility, Advanced Centre for Treatment Research and Education in Cancer (ACTREC) Tata Memorial Centre Navi Mumbai India

Abstract

Abstract14‐3‐3σ functions as an oncogene in colorectal cancer and is associated with therapy resistance. However, the mechanisms underlying these observations are not clear. The results in this report demonstrate that loss of 14‐3‐3σ in colorectal cancer cells leads to a decrease in tumor formation and increased sensitivity to chemotherapy. The increased sensitivity to chemotherapy is due to a decrease in the expression of UPR pathway genes in the absence of 14‐3‐3σ. 14‐3‐3σ promotes expression of the UPR pathway genes by binding to the transcription factor YY1 and preventing the nuclear localization of YY1. YY1, in the absence of 14‐3‐3σ, shows increased nuclear localization and binds to the promoter of the UPR pathway genes, resulting in decreased gene expression. Similarly, a YY1 mutant that cannot bind to 14‐3‐3σ also shows increased nuclear localization and is enriched on the promoter of the UPR pathway genes. Finally, inhibition of the UPR pathway with genetic or pharmacological approaches sensitizes colon cancer cells to chemotherapy. Our results identify a novel mechanism by which 14‐3‐3σ promotes tumor progression and therapy resistance in colorectal cancer by maintaining UPR gene expression.

Funder

Tata Memorial Centre

Science and Engineering Research Board

Publisher

Wiley

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