THOC3 interacts with YBX1 to promote lung squamous cell carcinoma progression through PFKFB4 mRNA modification

Abstract

The THO complex (THOC) is ubiquitously involved in RNA modification and various THOC proteins have been reported to regulate tumor development. However, the role of THOC3 in lung cancer remains unknown. In this study, we identified that THOC3 was highly expressed in lung squamous cell carcinoma (LUSC) and negatively associated with prognosis. THOC3 knockdown inhibited LUSC cell growth, migration, and glycolysis. THOC3 expression was regulated by TRiC proteins, such as CCT8 and CCT6A, which supported protein folding. Furthermore, THOC3 could form a complex with YBX1 to promote PFKFB4 transcription. THOC3 was responsible for exporting PFKFB4 mRNA to the cytoplasm, while YBX1 ensured the stability of PFKFB4 mRNA by recognizing m5C sites in its 3′UTR. Downregulation of PFKFB4 suppressed the biological activities of LUSC. Collectively, these findings suggest that THOC3, folded by CCT proteins can collaborate with YBX1 to maintain PFKFB4 expression and facilitate LUSC development. Therefore, THOC3 could be considered as a novel promising therapeutic target for LUSC.

The role of molecular chaperone CCT/TRiC in translation elongation: A literature review

“…Relevant studies have shown that CCT interacts with THOC3, and CCT8, CCT6A, and CCT2 are the first three proteins associated with THOC3. Abnormal expression of THOC can alter the quality control of mRNA output and affect transcription [ 89 ]. Further studies will reveal the exact role of CCT in nuclear protein folding, transport, and/or nuclear pore function, as well as the interaction of CCT with epigenetic modified proteins of the nascent polypeptide chain, thereby promoting the extension of the nascent polypeptide chain, i.e.…”

Y-Box Binding Protein 1: Unraveling the Multifaceted Role in Cancer Development and Therapeutic Potential

“…THOC3, regulated by CCT proteins, partners with YBX1 to support PFKFB4 expression, promoting lung squamous cell carcinoma (LUSC) progression [142]. YBX1's role in stabilizing PFKFB4 mRNA emphasizes its significance in this mechanism, highlighting its association with THOC3 (THO Complex Subunit 3) in LUSC development.…”

Comprehensive pan-cancer analysis of YBX family reveals YBX2 as a potential biomarker in liver cancer

“…The transcriptional regulation of YBX1 has been demonstrated to induce epithelial-mesenchymal transition (EMT) in various cancers (9,15). Moreover, extensive research has presented compelling evidence highlighting the pivotal involvement of YBX1 in the progression, metastasis, and development of drug resistance across diverse cancer types, including lung squamous cell carcinoma, intrahepatic cholangiocarcinoma, hepatocellular carcinoma (HCC), renal cell carcinoma, and nasopharyngeal carcinoma (16)(17)(18)(19)(20)(21). It has also been reported that YBX2 is correlated with the stemness, chemoresistance, malignancy and prognosis of endometrial cancer and lung cancer (22)(23)(24)(25)(26).…”