Berberine promotes IGF2BP3 ubiquitination by TRIM21 to induce G1/S phase arrest in colorectal cancer cells

Colorectal cancer (CRC) is the third most common cancer in the world and also the second leading cause of cancer death [1,2]. About half of patients with localized CRC eventually develop metastasis, which is a huge global public health burden [3]. The main treatment for CRC is surgical resection combined with adjuvant chemotherapy [4]. However, chemotherapy has defects such as systemic toxicity and acquired drug resistance, so the development of targeted drugs is urgently needed and has become a research hot spot [5].

Natural products not only have many targets and few side effects, but also have significant anti-cancer pharmacological activities [6,7]. For example, berberine (BBR), one of the most important active ingredients in Coptidis Rhizoma, has various pharmacological activities such as anti-tumor and anti-inflammatory [8,9]. In clinical practice, BBR can reduce the risk of colorectal adenoma and polypoid lesions in patients after polypectomy, although the underlying mechanism has not been clarified [10].

IGF2BP3, an oncofetoprotein, is a member of IGF2 mRNA-binding protein family (IGF2BPS) [11,12]. IGF2BP3 binds to mRNA containing N6-methyladenosine (m6A) and increases its stability [13,14]. IGF2BP3 is highly expressed in a variety of cancers and is an important biomarker and a potential candidate target for tumor therapy [15,16]. Previous study [17] has found that the anti-CRC activity of BBR may arise from its ability to downregulate IGF2BP3, but the detailed mechanism of action is unclear. TRIM21 is a ring-dependent E3 ubiquitin ligase [18,19]. TRIM21 can cause ubiquitination of cancer-related proteins which will further be degraded by ubiquitin-proteasome system (UPS). This may be detrimental to cancer development or inhibit cancer proliferation [20]. The importance of TRIM21 in cancer proliferation suggests its potential as a cancer therapeutic target [21].

In this study, we evaluated the effect of BBR on inhibiting the proliferation of colorectal cancer, and meanwhile elucidated the mechanism of how BBR acted on CRC via the downregulation of IGF2BP3. Our research provided theoretical basis and also novel research ideas for the development of safe and effective natural product-based anti-CRC drugs.

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