TEAD2 Promotes Hepatocellular Carcinoma Development and Sorafenib Resistance via TAK1 Transcriptional Activation.

Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer, yet the effectiveness of treatment for patients with HCC is significantly hindered by the development of drug resistance to sorafenib. Through the application of accessibility sequencing to examine drug-resistant HCC tissues, we identified substantial alterations in chromatin accessibility in sorafenib-resistant patient-derived xenograft models. Employing multiomics data integration analysis, we confirmed that the key transcription factor TEAD2, which plays an important role in the Hippo signaling pathway, is a key factor in regulating sorafenib resistance in HCC. Functional assays illustrated that TEAD2 plays a role in promoting HCC progression and enhancing resistance to sorafenib. Mechanistically, we demonstrated that TEAD2 binds to the TAK1 promoter to modulate its expression. Furthermore, we established the involvement of TAK1 in mediating TEAD2-induced sorafenib resistance in HCC, a finding supported by the effectiveness of TAK1 inhibitors. Our research highlights that targeting the TEAD2-TAK1 axis can effectively mitigate drug resistance in patients with HCC receiving sorafenib treatment, offering a novel approach for enhancing the treatment outcomes and prognosis of individuals with HCC. Implications: Targeting the TEAD2-TAK1 axis presents a promising therapeutic strategy to overcome sorafenib resistance in HCC, potentially improving treatment outcomes and prognosis for patients.

Zhang Y ，Ren Y ，Dong G ，Jiao Q ，Guo N ，Gao P ，Li Y ，Wang Y ，Zhao W ... -  《-》

Decreased lncRNA HNF4A-AS1 facilitates resistance to sorafenib-induced ferroptosis of hepatocellular carcinoma by reprogramming lipid metabolism.

Background: Resistance to sorafenib remains a major challenge in the systemic therapy of liver cancer. However, the involvement of lipid metabolism-related lncRNAs in this process remains unclear. Methods: Different expression levels of lipid metabolism-related lncRNAs in HCC were compared by analysis of Gene Expression Omnibus and The Cancer Genome Atlas databases. The influence of HNF4A-AS1 on sorafenib response was evaluated through analysis of public biobanks, cell cytotoxicity and colony formation assays. The effect of HNF4A-AS1 on sorafenib-induced ferroptosis was measured using lipid peroxidation, glutathione, malondialdehyde, and ROS levels. Furthermore, bioinformatic analyses and lipidomic profiling were conducted to study HNF4A-AS1 involvement in lipid metabolic reprogramming. Mechanistic experiments, including the luciferase reporter assay, RNA pulldown, RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), and RNA remaining assays, were employed to uncover the downstream targets and regulatory mechanisms of HNF4A-AS1 in sorafenib resistance in HCC. Xenograft and organoid experiments were carried out to assess the impact of HNF4A-AS1 on sorafenib response. Results: Bioinformatics analysis revealed that HNF4A-AS1, a lipid metabolism-related lncRNA, is specifically high-expressed in the normal liver and associated with sorafenib resistance in HCC. We further confirmed that HNF4A-AS1 was downregulated in HCC cells and organoids that resistant to sorafenib. Moreover, both in vitro and in vivo studies demonstrated that HNF4A-AS1 overexpression reversed sorafenib resistance in HCC cells, which was further enhanced by polyunsaturated fatty acids (PUFA) supplementation. Mechanistically, HNF4A-AS1 interacted with METTL3, leading to m6A modification of DECR1 mRNA, which subsequently decreased DECR1 expression via YTHDF3-dependent mRNA degradation. Consequently, decreased HNF4A-AS1 levels caused DECR1 overexpression, leading to decreased intracellular PUFA content and promoting resistance to sorafenib-induced ferroptosis in HCC. Conclusions: Our results indicated the pivotal role of lipid metabolism-related and liver-specific HNF4A-AS1 in inhibiting sorafenib resistance by promoting ferroptosis and suggesting that HNF4A-AS1 might be a potential target for HCC.

Zhao Y ，Han S ，Zeng Z ，Zheng H ，Li Y ，Wang F ，Huang Y ，Zhao Y ，Zhuo W ，Lv G ，Wang H ，Zhao G ，Zhao E ，Hu Y ，Hu P ，Zhao G ... -  《Theranostics》

5-methylcytosine methylation of MALAT1 promotes resistance to sorafenib in hepatocellular carcinoma through ELAVL1/SLC7A11-mediated ferroptosis.

Emerging evidence demonstrates that long non-coding RNAs (lncRNAs) play a crucial role in sorafenib resistance in hepatocellular carcinoma (HCC), and lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a dysregulated lncRNA in sorafenib-resistant HCC cells. However, the underlying regulatory mechanisms of MALAT1 in sorafenib-resistant HCC cells remain unclear. In the present study, we demonstrated that 5-methylcytosine (m5C) methylation catalyzed by NSUN2 and ALYREF contributed to the RNA stability and upregulation of MALAT1. The NSUN2/ALYREF/MALAT1 signaling axis was activated in sorafenib-resistant cells, and the upregulation of MALAT1 inhibited sorafenib-induced ferroptosis to drive sorafenib resistance. Mechanistically, MALAT1 maintained the mRNA stability of SLC7A11 by directly binding to ELAVL1 and stimulating its cytoplasmic translocation. Furthermore, we explored a new synergetic strategy for the treatment of HCC by combining MALAT1 inhibitor MALAT1-IN1 with sorafenib. The results demonstrated that MALAT1-IN1 significantly enhanced sorafenib efficacy for the treatment of HCC both in vitro and in vivo. Collectively, our work brings new insights into the epigenetic mechanisms of sorafenib resistance and offers an alternative therapeutic strategy targeting ferroptosis for sorafenib-resistant HCC patients.

Shi CJ ，Pang FX ，Lei YH ，Deng LQ ，Pan FZ ，Liang ZQ ，Xie T ，Wu XL ，Wang YY ，Xian YF ，Zeng WQ ，Lin HL ，Zhang JF ... -  《-》

The novel role of LOC344887 in the enhancement of hepatocellular carcinoma progression via modulation of SHP1-regulated STAT3/HMGA2 signaling axis.

Pseudogene-derived long non-coding RNAs (lncRNAs) have become crucial regulators in cancer progression. Extensive research highlights the pivotal role of signal transducer and activator of transcription 3 (STAT3) in promoting hepatocellular carcinoma (HCC) progression. As a result, targeting aberrant STAT3 activation presents a promising therapeutic strategy for HCC. Our study aims to identify the key pseudogene-derived lncRNA involved in modulating STAT3 activation and driving HCC progression. Our study is the first to identify a significant upregulation of LOC344887, a pseudogene-derived lncRNA, in HCC tissues. Elevated LOC344887 levels correlated with poor overall survival (OS) and recurrence-free survival (RFS), highlighting its potential as a biomarker for HCC. The rapid amplification of cDNA ends (RACE) and RT-PCR experiments revealed the expression of a novel LOC344887 transcript, named LOC344887-v2, alongside the annotated RefSeq transcript NR_151491 (LOC344887-v1) in both HCC tissues and hepatoma cell lines. Functional assays demonstrated that LOC344887 enhances cellular migration and invasion, with its variant LOC344887-v2 exhibiting a more pronounced effect. Further, LOC344887 mechanistically regulates STAT3 phosphorylation at tyrosine 705, which is crucial for maintaining STAT3 activation in HCC. Our findings unravel that LOC344887 not only physically interacts with p-STAT3 but also prevents its dephosphorylation by src homology region 2 domain-containing phosphatase 1 (SHP-1), thereby sustaining oncogenic signaling. In addition, we identified HMGA2 as a target of the LOC344887/SHP-1/STAT3 axis, with higher HMGA2 expression correlating with poorer prognosis in HCC patients. The ability of LOC344887 to regulate HMGA2 through direct binding of STAT3 to its promoter underlines its role in HCC progression. Collectively, these findings elucidate a novel oncogenic role of LOC344887 in HCC and suggest that targeting this lncRNA and its associated pathways may provide novel therapeutic strategies for improving patient outcomes in HCC.

Lin YH ，Chi HC ，Wu MH ，Liao CJ ，Chen CY ，Huang PS ，Huang WC ，Wang YW ，Lin TK ，Lai MW ，Yeh CT ，Lin KH ... -  《International Journal of Biological Sciences》

Sorafenib and SIAIS361034, a novel PROTAC degrader of BCL-x(L), display synergistic antitumor effects on hepatocellular carcinoma with minimal hepatotoxicity.

The overexpression of BCL-xL is closely associated with poor prognosis in hepatocellular carcinoma (HCC). While the strategy of combination of BCL-xL and MCL-1 for treating solid tumors has been reported, it presents significant hepatotoxicity. SIAIS361034, a novel proteolysis targeting chimera (PROTAC) agent, selectively induces the ubiquitination and subsequent proteasomal degradation of BCL-xL through the CRBN-E3 ubiquitin ligase. When combined with sorafenib, SIAIS361034 showed a potent synergistic effect in inhibiting hepatocellular carcinoma development both in vitro and in vivo. Since SIAIS361034 exhibits a high degree of selectivity for degrading BCL-xL in hepatocellular carcinoma, the hepatotoxicity typically associated with the combined inhibition of BCL-xL and MCL-1 is significantly reduced, thereby greatly enhancing safety. Mechanistically, BCL-xL and MCL-1 sequester the BH3-only protein BIM on mitochondria at baseline. Treatment with SIAIS361034 and sorafenib destabilizes BIM/BCL-xL and BIM/MCL1 association, resulting in the liberation of more BIM proteins to trigger apoptosis. Additionally, we discovered a novel compensatory regulation mechanism in hepatocellular carcinoma cells. BIM can rapidly respond to changes in the balance between BCL-xL and MCL-1 through their co-transcription factor MEF2C to maintain apoptosis resistance. In summary, the combination therapy of SIAIS361034 and sorafenib represents an effective and safe approach for inhibiting hepatocellular carcinoma progression. The novel balancing mechanism may also provide insights for combination and precision therapies in the treatment of hepatocellular carcinoma.

Zhang X ，Tao Y ，Xu Z ，Jiang B ，Yang X ，Huang T ，Tan W ... -  《-》