Non-POU Domain-Containing Octomer-Binding (NONO) protein expression and stability promotes the tumorigenicity and activation of Akt/MAPK/β-catenin pathways in human breast cancer cells

Sep 24, 2026

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Breast cancer is a leading cause of cancer mortality, requiring new therapeutic targets. Non-POU domain-containing octamer-binding (NONO) protein is reported to be overexpressed in breast cancer, with the WW domain of PIN1 validated to bind NONO’s c-terminal thr-pro motifs. This interaction stabilizes NONO by blocking proteasomal degradation and positions PIN1 as a positive regulator of breast tumor development. NONO silencing suppresses growth, survival, migration, invasion, EMT and stemness in vitro, while also reducing metastatic capability in vivo. Mechanistically, NONO depletion elevates PDL1 and activates Akt/MAPK/β-catenin signaling, supporting NONO as a potential anti-cancer drug target.

LanguageEnglish

CategoryHealthcare

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Pages24

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Abstract

Background

Breast cancer burden and treatment limitations

Role and localization of NONO

NONO interactions and functions

Lone et al. Cell Communication and Signaling (2023) 21:157 [https://doi.org/10.1186/s12964-023-01179-0](https://doi.org/10.1186/s12964-023-01179-0) Cell Communication and Signaling RESEARCH Open Access Non-POU Domain-Containing Octomer-Binding (NONO) protein expression and stability promotes the tumorigenicity and activation of Akt/MAPK/β-catenin pathways in human breast cancer cells Bilal Ahmad Lone1, Fouzia Siraj2, Ira Sharma2, Shweta Verma3,4, Shibendra Kumar Lal Karna 1, Faiz Ahmad1, Preeti Nagar 1, Chetana Sachidanandan3,4 andYuba Raj Pokharel 1* Abstract Breast cancer is one of the most common cancers with a high mortality rate, underscoring the need to identify new therapeutic targets. Here we report that non-POU domain-containing octamer-binding (NONO) protein is overexpressed in breast cancer and validated the interaction of the WW domain of PIN1 with c-terminal threonine-proline (thr-pro) motifs of NONO. The interaction of NONO with PIN1 increases the stability of NONO by inhibiting its proteasomal degradation, and this identifies PIN1 as a positive regulator of NONO in promoting breast tumor development. Functionally, silencing of NONO inhibits the growth, survival, migration, invasion, epithelial to mesenchymal transition (EMT), and stemness of breast cancer cells in vitro. A human metastatic breast cancer cell xenograft was established in transparent zebrafish (Danio rerio) embryos to study the metastatic inability of NONO-silenced breast cancer cells in vivo. Mechanistically, NONO depletion promotes the expression of the PDL1 cell-surface protein in breast cancer cells. The identification of novel interactions of NONO with c-Jun and β-catenin proteins and activation of the Akt/ MAPK/β-catenin signaling suggests that NONO is a novel regulator of Akt/MAPK/β-catenin signaling pathways. Taken together, our results indicated an essential role of NONO in the tumorigenicity of breast cancer and could be a potential target for anti-cancerous drugs. Keywords Breast cancer, NONO, PIN1, MAPK/β-catenin, P53, Metastasis, Apoptosis, Cancer stem cells *Correspondence: Yuba Raj Pokharel[yrp@sau.ac.in](yrp@sau.ac.in) 1 Cancer Biology Laboratory, Faculty of Life Science and Biotechnology, South Asian University, Rajpur Road, Maidangarhi, New Delhi 110068, India 2 National Institute of Pathology, Safdarjung Hospital Campus, Room No. 610, 6th Floor, Ansari Nagar, New Delhi 110029, India 3 CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi 110025, India 4 Academy of Scientific and Innovative Research (AcSIR), Gaziabad 201002, India Background With an estimated 2.3 million new cases, breast cancer is the most frequently diagnosed type of cancer worldwide [1]. It has a high recurrence rate and a tendency to metastasize, which is consistent with the pathological conditions [2]. Once metastasized, the cancer cells develop stemness and become more resistant to apoptosis, making treatment more challenging [3, 4]. Therapeutic strategies for breast cancer have improved significantly; however, patients with distant metastatic breast cancer are less responsive to standard therapies. Although © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of

FAQs

What is the main finding about NONO in breast cancer?

NONO is overexpressed in breast cancer and is linked to tumorigenicity through activation of Akt/MAPK/β-catenin pathways. Silencing NONO reduces multiple malignant phenotypes in cells and impairs metastatic capability in vivo.

How does PIN1 regulate NONO according to the study?

The WW domain of PIN1 binds the c-terminal thr-pro motifs of NONO. This interaction increases NONO stability by inhibiting its proteasomal degradation, making PIN1 a positive regulator of NONO-driven tumor development.

Which downstream mechanisms are implicated when NONO is depleted?

NONO depletion promotes PDL1 expression on the cell surface and is associated with activation of Akt/MAPK/β-catenin signaling. The study also identifies novel interactions of NONO with c-Jun and β-catenin.

Sep 24, 2026

Uploaded by Jacob