SMYD3 Impedes Small Cell Lung Cancer Sensitivity to Alkylation Damage through RNF113A Methylation-Phosphorylation Cross-talk.

Small cell lung cancer (SCLC) is the most fatal form of lung cancer, with dismal survival, limited therapeutic options, and rapid development of chemoresistance. We identified the lysine methyltransferase SMYD3 as a major regulator of SCLC sensitivity to alkylation-based chemotherapy. RNF113A methylation by SMYD3 impairs its interaction with the phosphatase PP4, controlling its phosphorylation levels. This cross-talk between posttranslational modifications acts as a key switch in promoting and maintaining RNF113A E3 ligase activity, essential for its role in alkylation damage response. In turn, SMYD3 inhibition restores SCLC vulnerability to alkylating chemotherapy. Our study sheds light on a novel role of SMYD3 in cancer, uncovering this enzyme as a mediator of alkylation damage sensitivity and providing a rationale for small-molecule SMYD3 inhibition to improve responses to established chemotherapy. SCLC rapidly becomes resistant to conventional chemotherapy, leaving patients with no alternative treatment options. Our data demonstrate that SMYD3 upregulation and RNF113A methylation in SCLC are key mechanisms that control the alkylation damage response. Notably, SMYD3 inhibition sensitizes cells to alkylating agents and promotes sustained SCLC response to chemotherapy. This article is highlighted in the In This Issue feature, p. 2007.

Lukinović V ，Hausmann S ，Roth GS ，Oyeniran C ，Ahmad T ，Tsao N ，Brickner JR ，Casanova AG ，Chuffart F ，Benitez AM ，Vayr J ，Rodell R ，Tardif M ，Jansen PWTC ，Couté Y ，Vermeulen M ，Hainaut P ，Mazur PK ，Mosammaparast N ，Reynoird N ... -  《-》

Methyltransferases in cancer drug resistance: Unlocking the potential of targeting SMYD3 to sensitize cancer cells.

Drug resistance is a significant challenge in oncology and is driven by various mechanisms, among which a crucial role is played by enhanced DNA repair. Thus, targeting DNA damage response (DDR) factors with specific inhibitors is emerging as a promising therapeutic strategy. An important process involved in the modulation of DNA repair pathways, and hence in drug resistance, is post-translational modification (PTM). PTMs such as methylation affect protein function and are critical in cancer biology. Methylation is catalyzed by specific enzymes called protein methyltransferases. In recent years, the SET domain-containing N-lysine methyltransferase SMYD3 has emerged as a significant oncogenic driver. It is overexpressed in several tumor types and plays a signal-dependent role in promoting gastrointestinal cancer formation and development. Recent evidence indicates that SMYD3 is involved in the maintenance of cancer genome integrity and contributes to drug resistance in response to genotoxic stress by regulating DDR mechanisms. Several potential SMYD3 interactors implicated in DNA repair, especially in the homologous recombination and non-homologous end-joining pathways, have been identified by in silico analyses and confirmed by experimental validation, showing that SMYD3 promotes DDR protein interactions and enzymatic activity, thereby sustaining cancer cell survival. Targeting SMYD3, in combination with standard or targeted therapy, shows promise in overcoming drug resistance in colorectal, gastric, pancreatic, breast, endometrial, and lung cancer models, supporting the integration of SMYD3 inhibition into cancer treatment regimens. In this review, we describe the role played by SMYD3 in drug resistance and analyze its potential as a molecular target to sensitize cancer cells to treatment.

Sanese P ，Fasano C ，Lepore Signorile M ，De Marco K ，Forte G ，Disciglio V ，Grossi V ，Simone C ... -  《-》

SMYD3 plays a pivotal role in mediating the epithelial-mesenchymal transition process in breast cancer.

In previous reports, we highlighted the significant involvement of SMYD3, a histone methyltransferase (HMT), in various aspects of cancer progression, including cell adhesion, migration, and invasion. In this study, we delved deeper into understanding the relationship between SMYD3 and epithelial-mesenchymal transition (EMT) both in cell lines and clinical samples. Our investigation uncovered a notable correlation between heightened SMYD3 expression and the presence of EMT markers in human breast cancer tissues. We found that the induction of SMYD3 expression is facilitated by transforming growth factor beta 1 (TGF-β1), which achieves this by suppressing miR-124, an inhibitor that targets SMYD3, through alterations in DNA methylation. Conversely, our experiments demonstrated that reducing SMYD3 levels through RNA interference impeded TGF-β1-induced EMT in breast cancer cells. Furthermore, our results revealed that SMYD3 alone has the capability to modulate the expression of markers associated with EMT. An intriguing aspect of our study is the revelation that SMYD3 influences the activation of vimentin by binding to its response elements within the core promoter region. Notably, this effect is independent of SMYD3's histone methyltransferase activity. These findings collectively underscore the pivotal role of SMYD3 in driving EMT, both in cell lines and primary cancer tissues, particularly emphasizing its significance in TGF-β1-induced EMT in breast cancer.

Zhao WW ，Gao Y ，Zhu YT ，Zhong FL ，Luo XG ... -  《-》

Adaptor protein CEMIP reduces the chemosensitivity of small cell lung cancer via activation of an SRC-YAP oncogenic module.

Small cell lung cancer (SCLC) is a recalcitrant malignancy with dismal prognosis due to rapid relapse after an initial treatment response. More effective treatments for SCLC are desperately needed. Our previous studies showed that cell migration-inducing hyaluronan binding protein (CEMIP) functionally promotes SCLC cell proliferation and metastasis. In this study, we investigated whether and how CEMIP regulates the chemosensitivity of SCLC. Through the GDSC database, we found that CEMIP expression levels were positively correlated with the IC50 values of several commonly used chemotherapeutic drugs in SCLC cells (cisplatin, gemcitabine, 5-fluorouracil and cyclophosphamide). We demonstrated that overexpression or knockdown of CEMIP in SCLC cells resulted in a notable increase or reduction in the IC50 value of cisplatin or etoposide, respectively. We further revealed that CEMIP functions as an adaptor protein in SCLC cells to interact with SRC and YAP through the 1-177 aa domain and 820-1361 aa domain, respectively, allowing the autophosphorylation of Y416 and activation of SRC, thus facilitating the interaction between YAP and activated SRC, and resulting in increased phosphorylation of Y357, protein stability, nuclear accumulation and transcriptional activation of YAP. Overexpressing SRC or YAP counteracted the CEMIP knockdown-mediated increase in the sensitivity of SCLC cells to cisplatin and etoposide. The combination of the SRC inhibitor dasatinib or the YAP inhibitor verteporfin and cisplatin/etoposide (EP regimen) displayed excellent synergistic antitumor effects on SCLC both in vitro and in vivo. This study demonstrated that targeted therapy against the CEMIP/SRC/YAP complex is a potential strategy for SCLC and provides a rationale for the development of future clinical trials with translational prospects.

Shen XJ ，Wei HL ，Mo XC ，Mo XX ，Li L ，He JC ，Wei XY ，Qin XJ ，Xing SP ，Luo Z ，Chen ZQ ，Yang J ... -  《-》

Transcriptional regulatory network analysis identifies GRN as a key regulator bridging chemotherapy and immunotherapy response in small cell lung cancer.

Small cell lung cancer (SCLC) is an aggressive and heterogeneous subtype, representing 15% of lung cancer cases. Although SCLC initially responds to etoposide and platinum (EP) chemotherapy, nearly all patients relapse with resistant tumors. While recent advances in immunotherapy have shown promise, only 10-20% of patients benefit, and effective stratification methods are lacking. The mechanisms of resistance to both therapeutics remain obscure. In this study, we aimed to gain insights into those leveraging a recent surge in the field of SCLC genomics. We constructed a regulatory network for SCLC and identified granulin precursor (GRN) as a hub of EP response associated genes. GRN-low patients showed improved survival with chemotherapy, while GRN-high patients exhibited resistance. GRN overexpression in SCLC cells conferred resistance to EP treatment and suppressed neuroendocrine features. GRN and its associated genes were linked to cancer cell intrinsic immunogenicity, and single-cell RNA-seq data revealed that GRN expression is particularly high in subsets of tumor-associated macrophages. In concordance with these findings, GRN-low tumors showed significantly better survival with chemo-immunotherapy, while GRN-high tumors did not benefit from additional immunotherapy. GRN-high tumors, associated with non-neuroendocrine (non-NE) subtypes, had a higher level of macrophage infiltration, potentially contributing to immunotherapy resistance. These results highlight GRN as a critical regulator of chemo-resistance and a potential biomarker for immunotherapy resistance in SCLC. Targeted therapeutic strategies for GRN-low patients could improve outcomes, while new approaches are needed for GRN-high patients. Overall, our findings implicate GRN as a bridge between chemotherapy and immunotherapy resistance through GRN-mediated mechanisms.

Yoo S ，Patel AS ，Karam S ，Zhong Y ，Wang L ，Jiang F ，Kong R ，Bikvan S ，Wang W ，Sinha A ，Powell CA ，Zhu J ，Watanabe H ... -  《Journal of Hematology & Oncology》