SHARPIN is a novel gene of colorectal cancer that promotes tumor growth potentially via inhibition of p53 expression - Abstract - International Journal of Oncology 65

Sep 21, 2026

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Colorectal cancer (CRC) is highly prevalent and drives substantial cancer-related mortality, creating an urgent need to improve CRC treatment. E3 ubiquitin ligases regulate protein levels through posttranslational ubiquitin-mediated proteolysis and have been linked to cancer progression. Using spatial transcriptomics and single-cell RNA sequencing in clinical CRC datasets, SHARPIN was identified on amplified 8q and found upregulated in tumor cells. Elevated SHARPIN correlated with lymphatic invasion and predicted poor prognosis independently. SHARPIN overexpression increased MDM2, downregulating p53, whereas SHARPIN loss reduced MDM2 and increased p53, impacting cell cycle progression, apoptosis, and tumor growth, supporting SHARPIN as a therapeutic target.

LanguageEnglish

CategoryResearch & Report

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Pages18

Reading Time45 min

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Abstract

Introduction

Ubiquitin-proteasome system and E1/E2/E3

E3 ubiquitin ligases in cancer and target discovery

LUBAC complex and SHARPIN

INTERNATIONAL JOURNAL OF ONCOLOGY 65: 113, 2024 SHARPINis a novel gene of colorectal cancer that promotes tumor growth potentially via inhibition of p53 expression YUSUKE NAKANO 1,2 , TAKAAKI MASUDA 1,3 , TAKEHARU SAKAMOTO4 , NORITAKA TANAKA4 , TARO TOBO5 , MASAHIRO HASHIMOTO 1,2 , TAKANARI TATSUMI 1 , HIDEYUKI SAITO 1 , JUNICHI TAKAHASHI 1 , KENSUKE KOIKE 1 , TADASHI ABE 1 , YUKI ANDO 1 , YUKI OZATO 1,2 , KIYOTAKA HOSODA 1 , KOSUKE HIROSE 1 , SATOSHI HIGUCHI 1,2 , TOMOHIKO IKEHARA 1 , YUICHI HISAMATSU 1 , TAKEO TOSHIMA 1 , YUSUKE YONEMURA 1 , TAKAYUKI OGINO2 , MAMORU UEMURA2 , HIDETOSHI EGUCHI2 , YUICHIRO DOKI2 and KOSHI MIMORI 1 1Department of Surgery, Kyushu University Beppu Hospital, Oita 874‑0838, Japan; 2Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565‑0871, Japan; 3Department of Breast and Endocrine Surgery, Kochi Medical School, Kochi University, Nankoku 783‑8505, Japan; 4Department of Cancer Biology, Institute of Biomedical Science, Kansai Medical University, Osaka 573‑1010, Japan; 5Department of Clinical Laboratory Medicine, Kyushu University Beppu Hospital, Oita 874‑0838, Japan Received February 13, 2024; Accepted September 26, 2024 DOI: 10.3892/ijo.2024.5701 Abstract. Colorectal cancer (CRC) is widely prevalent and represents a significant contributor to global cancer‑related mortality. There remains a pressing demand for advance‑ ments in CRC treatment modalities. The E3 ubiquitin ligase is a critical enzyme involved in modulating protein expression levels via posttranslational ubiquitin‑mediated proteolysis, and it is reportedly involved in the progression of various cancers, making it a target of recent interest in anticancer therapy. In the present study, using comprehensive expression analysis involving spatial transcriptomic analysis with single‑cell RNA sequencing in clinical CRC datasets, the ubiquitin‑associated protein Shank‑associated RH domain interactor (SHARPIN) was identified, located on amplified chromosome 8q, which could promote CRC progression. SHARPIN was found to be upregulated in tumor cells, with elevated expression observed in tumor tissues. This heightened expression of SHARPIN was positively associated with lymphatic invasion and served as an independent predictor of a poor prognosis in patients with CRC. In vitro and in vivo analyses using SHARPIN‑overexpressing or ‑knockout CRC cells revealed that SHARPIN overexpression upregulated MDM2, resulting in the downregulation of p53, while SHARPIN silencing or knockout downregulated MDM2, leading to p53 upregulation, which affects cell cycle progression, Correspondence to: Professor Koshi Mimori, Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumibaru, Oita 874‑0838, Japan E‑mail: mimori.koshi.791@m.kyushu‑[u.ac.jp](u.ac.jp) Key words: colorectal cancer, shank‑associated RH domain interactor, novel gene, p53, ubiquitin‑proteasome system tumor cell apoptosis and tumor growth in CRC. Furthermore, SHARPIN was found to be overexpressed in several cancer types, exerting significant effects on survival outcomes. In conclusion, SHARPIN represents a newly identified novel gene with the potential to promote tumor growth following apoptosis inhibition and cell cycle progression in part by inhibiting p53 expression via MDM2 upregulation; therefore, SHARPIN represents a potential therapeutic target for CRC. Introduction The ubiquitin (Ub)‑proteasome system (UPS) is a complex and essential cellular machinery responsible for regulating protein expression levels by degrading intracellular proteins in eukaryotic cells (1) . This system plays a pivotal role in maintaining cellular homeostasis by controlling the concen‑ tration of specific proteins, thus ensuring the timely removal of misfolded, damaged, or no longer needed proteins (2) . The UPS plays crucial roles in multiple essential cellular processes, such as advancing the cell cycle, transmitting signals, repairin

FAQs

What role does SHARPIN play in colorectal cancer progression?

SHARPIN promotes CRC progression and is upregulated in tumor cells. Higher expression is linked to lymphatic invasion and poor prognosis.

How does SHARPIN influence p53 signaling?

SHARPIN overexpression increases MDM2, leading to p53 downregulation. SHARPIN silencing or knockout decreases MDM2 and increases p53.

What evidence supports SHARPIN as a potential therapeutic target?

In vitro and in vivo analyses using SHARPIN-overexpressing or -knockout CRC cells show SHARPIN affects MDM2/p53 and thereby cell cycle progression, apoptosis, and tumor growth.

Sep 21, 2026

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