Ferroptosis is a newly defined form of regulated cell death characterized by the irondependent accumulation of lipid hydroperoxides. Erastin, the ferroptosis activator, binds to voltage-dependent anion channels VDAC2 and VDCA3, but treatment with erastin can result in the degradation of the channels. Here, the authors show that Nedd4 is induced following erastin treatment, which leads to the ubiquitination and subsequent degradation of the channels. Depletion of Nedd4 limits the protein degradation of VDAC2/3, which increases the sensitivity of cancer cells to erastin. By understanding the molecular mechanism of erastin-induced cellular resistance, we can discover how cells adapt to new molecules to maintain homeostasis. Furthermore, erastin-induced resistance mediated by FOXM1-Nedd4-VDAC2/3 negative feedback loop provides an initial framework for creating avenues to overcome the drug resistance of ferroptosis activators.

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Melanoma, the most aggressive skin cancer, is mainly treated with BRAF inhibitors or immunotheareapy. However, most patients who initially responded to BRAF inhibitors or immunotheareapy become resistant following relapse. Ferroptosis is a form of regulated cell death characterized by its dependence on iron ions and the accumulation of lipid reactive oxygen species (ROS). Recent studies have demonstrated that ferroptosis is a good method for tumor treatment, and iron homeostasis is closely associated with ferroptosis. Iron regulatory protein (IRP)1 and 2 play important roles in maintaining iron homeostasis, but their functions in ferroptosis have not been investigated. The present study reported that the expression of IRP1 and IRP2 was increased by the ferroptosis inducers erastin and RSL3 in melanoma cells. Depletion of IRP1 significantly suppressed erastin-and RSL3-induced ferroptosis. IRP2 had a weak effect but could enhance the promoting function of IRP1 on ferroptosis. Further, erastin and RSL3 promoted the transition of aconitase 1 to IRP1, which regulated downstream iron metabolism proteins, including transferrin receptor (TFRC), ferroportin (FPN) and ferritin heavy chain 1 (FTH1). Moreover, overexpression of TFRC and knockdown of FPN and FTH1 significantly promoted erastin-and RSL3-induced ferroptosis in IRP1 knockdown melanoma cells. Collectively, the present findings indicate that IRP1 plays an essential role in erastinand RSL3-induced ferroptosis by regulating iron homeostasis.

Autophagy is a self‐proteolytic process that degrades intracellular material to maintain cellular homeostasis. Transcription factor EB (TFEB) is the master activator that regulates the transcription of genes involved in autophagy and lysosomal biogenesis. However, the cotranscriptional factors of TFEB are rarely identified. Here, we found that Yin Yang 1 (YY1) regulated autophagy and lysosome biogenesis in melanoma cells. YY1 cooperates with TFEB to regulate autophagy through controlling the transcription of autophagy and lysosome biogenesis related genes. Moreover, suppression of YY1 enhanced the antitumor efficiency of vemurafenib both in vitro and in vivo. Collectively, these studies identify YY1 as a novel cotranscription factor of TFEB in regulating autophagy and lysosomal functions and suggest YY1 could be a therapeutic target in cancer treatment.

Sialic acid-binding Ig-like lectin 15, or Siglec-15, is identified as a critical immune suppressor. Siglec-15 expression is normally limited to certain myeloid cells, but it can be upregulated in a variety of tumors and on tumor-infiltrating myeloid cells. Siglec-15 significantly inhibits antigen-specific T cell responses both in vitro and in vivo. Conversely, genetic ablation of Siglec-15 promotes anti-tumor responses. Therefore, a Siglec-15-targeting blocking antibody could represent a novel class of anti-tumor immunotherapy. BCG008, a fully human monoclonal antibody antagonist of Siglec-15, was generated from RenMab™ mice, which contain the entire human immunoglobulin variable domain. Compared to a reference Siglec-15 blocking antibody (5G12), BCG008 exhibited higher affinity for human and cynomolgus monkey Siglec-15 and targeted distinct binding epitopes. In in vitro studies, BCG008 significantly abrogated Siglec-15-mediated T cell suppression in a dose-dependent manner, as measured by CD4+ and CD8+ T cell proliferation. Subsequently, the efficacy and safety of BCG008 was evaluated in syngeneic tumor models in Siglec15-humanized mice. BCG008 monotherapy significantly inhibited tumor growth, and the effect of the tumor inhibition was potentiated when administered in combination with other immune-checkpoint inhibitors, including anti-PD-L1 antibodies. In safety evaluation, BCG008 was well-tolerated in the tumor-bearing mice; no adverse effects were observed even at high doses (e.g. 30 mg/kg). Taken together, these results demonstrate that BCG008 is a novel anti-human Siglec-15 blocking antibody with favorable efficacy and safety profiles that can provide potential benefits for future cancer immunotherapy. Citation Format: Yongfei Yang, Aidong Qu, Fengping Yao, Pan Song, Hongyuan Liang, Maopeng Tian, Fang Yang, Zhaoxue Yu, Xu Zhou, Xiuling Li. BCG008, a human Siglec-15 blocking antibody, displays potent anti-tumor activity in Siglec-15-humanized mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6435.