Apoptosis‐inducing factor (AIF) plays a dual role in regulating cell survival and apoptosis, acting as a prosurvival factor in mitochondria via its NADH oxidoreductase activity and activating the caspase‐independent apoptotic pathway (i.e., parthanatos) after nuclear translocation. However, whether one factor conjunctively controls the separated functions of AIF is not clear. Here, it is shown that OTU deubiquitinase 1 (OTUD1) acts as a link between the two functions of AIF via deubiquitination events. Deubiquitination of AIF at K244 disrupts the normal mitochondrial structure and compromises oxidative phosphorylation, and deubiquitination of AIF at K255 enhances its DNA‐binding ability to promote parthanatos. Moreover, OTUD1 stabilizes DDB1 and CUL4 associated factor 10 (DCAF10) and recruits the cullin 4A (CUL4A)‐damage specific DNA binding protein 1 (DDB1) complex to promote myeloid cell leukemia sequence 1 (MCL1) degradation, thereby activating caspase‐dependent apoptotic signaling. Collectively, these results reveal the central role of OTUD1 in activating both caspase‐independent and caspase‐dependent apoptotic signaling and propose decreased OTUD1 expression as a key event promoting chemoresistance in esophageal squamous cell carcinoma.

Highlights d ARID1A stability is controlled by the ubiquitin-proteasome system d TRIM32 promotes squamous cell carcinoma progression by degrading ARID1A d USP11 prevents squamous cell carcinoma progression by stabilizing ARID1A d ARID1A loss activates SDC2 to drive squamous cell carcinoma development

Squamous cell carcinomas (SCC) constitute a group of human malignancies that originate from the squamous epithelium. Most SCC patients experience treatment failure and relapse and have a poor prognosis due to de novo and acquired resistance to first-line chemotherapeutic agents. To identify chemoresistance mechanisms and explore novel targets for chemosensitization, we performed whole-transcriptome sequencing of paired resistant and parental SCC cells. We identified DLGAP1 antisense RNA 2 (D-AS2) as a crucial noncoding RNA that contributes to chemoresistance in SCC. Mechanistically, D-AS2 affected chromatin accessibility around the histone mark H3K27ac of FAM3 metabolism regulating signaling molecule D (FAM3D), reducing FAM3D mRNA transcription and extracellular protein secretion. FAM3D interacted with the Gαi-coupled G protein-coupled receptors (GPCRs) formyl peptide receptor 1 (FPR1) and FPR2 to suppress phospholipase D (PLD) activity, and reduced FAM3D increased PLD signaling. Moreover, activated PLD promoted phosphatidic acid (PA) production and subsequent nuclear translocation of yes-associated protein (YAP). Accordingly, in vivo administration of a D-AS2-targeting antisense oligonucleotide sensitized SCC to cisplatin treatment. In summary, this study shows that D-AS2/FAM3D-mediated PLD/PA lipid signaling is essential for SCC chemoresistance, suggesting D-AS2 can be targeted to sensitize SCC to cytotoxic chemotherapeutic agents.

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Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complexes have a mutation rate of approximately 20% in human cancer, and ARID1A is the most frequently mutated component. However, some components of SWI/SNF complexes, including ARID1A, exhibit a very low mutation rate in squamous cell carcinoma (SCC), and their role in SCC remains unknown. Here, we demonstrate that the low expression of ARID1A in SCC is the result of promoter hypermethylation. Low levels of ARID1A were associated with a poor prognosis. ARID1A maintained transcriptional homeostasis through both direct and indirect chromatin-remodeling mechanisms. Depletion of ARID1A activated an oncogenic transcriptome that drove SCC progression. The anti-inflammatory natural product parthenolide was synthetically lethal to ARID1A-depleted SCC cells due to its inhibition of both HDAC1 and oncogenic signaling. These findings support the clinical application of parthenolide to treat patients with SCC with low ARID1A expression. Significance: This study reveals novel inactivation mechanisms and tumor-suppressive roles of ARID1A in SCC and proposes parthenolide as an effective treatment for patients with SCC with low ARID1A expression.

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Squamous cell carcinomas (SCCs) constitute a group of human malignancies that originate from the squamous epithelium. Most SCC patients experience treatment failure and relapse and have a poor prognosis due to de novo and acquired resistance to first-line chemotherapeutic agents. To identify chemoresistance mechanisms and explore novel chemosensitizer targets, we performed whole-transcriptome sequencing of paired resistant/parental SCC cells. We identified DLGAP1 antisense RNA 2 (D-AS2) as a crucial noncoding RNA that contributes to chemoresistance in SCC. Mechanistically, D-AS2 associates with histones to regulate the distal elements of FAM3 metabolism regulating signaling molecule D (FAM3D) and reduces extracellular FAM3D protein secretion. FAM3D interacts with Gαi-coupled G protein-coupled receptor (GPCR) formyl peptide receptor (FPR) 1 and FPR2 to suppress phospholipase D (PLD) activity; thus, reduced FAM3D activates PLD signaling. Moreover, activated PLD promotes phosphatidic acid (PA) production and subsequent yes-associated protein (YAP) nuclear translocation. Accordingly, in vivo administration of a D-AS2-targeting antisense oligonucleotide sensitizes SCC to cisplatin treatment. In summary, our study reveals that D-AS2/FAM3D-mediated PLD/PA lipid signaling is essential in SCC chemoresistance and that D-AS2 can be targeted to sensitize SCC to cytotoxic chemotherapeutic agents.