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Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD + metabolism influences both tissue ageing and cancer. However, the role of NAD + metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD + salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA–NAMPT–NAD + signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD + -mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD + metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD + augmentation should be administered with precision. Nacarelli et al. show that the nicotinamide-phosphoribosyltransferase-regulated NAD + biogenesis pathway promotes the proinflammatory senescence-associated secretory phenotype by enhancing glycolysis and mitochondrial respiration during senescence.

Alterations in components of the SWI/SNF chromatin-remodeling complex occur in ~20% of all human cancers. For example, is mutated in up to 62% of clear cell ovarian carcinoma (OCCC), a disease currently lacking effective therapies. Here we show that mutation creates a dependence on glutamine metabolism. SWI/SNF represses ( ) and ARID1A inactivation upregulates GLS1. ARID1A inactivation increases glutamine utilization and metabolism through the tricarboxylic acid cycle to support aspartate synthesis. Indeed, glutaminase inhibitor CB-839 suppresses the growth of mutant, but not wildtype, OCCCs in both orthotopic and patient-derived xenografts. In addition, glutaminase inhibitor CB-839 synergizes with immune checkpoint blockade anti-PDL1 antibody in a genetic OCCC mouse model driven by conditional inactivation. Our data indicate that pharmacological inhibition of glutaminase alone or in combination with immune checkpoint blockade represents an effective therapeutic strategy for cancers involving alterations in the SWI/SNF complex such as mutations.

CARM1 is often overexpressed in human cancers including in ovarian cancer. However, therapeutic approaches based on CARM1 expression remain to be an unmet need. Cancer cells exploit adaptive responses such as the endoplasmic reticulum (ER) stress response for their survival through activating pathways such as the IRE1α/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1α/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1α/XBP1s pathway was effective against ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model. Our data show that pharmacological inhibition of the IRE1α/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers. The unfolded protein response (UPR) promotes cell survival in cancers with hyperactive ER stress response. Here the authors show that CARM1, an arginine methyltransferase, controls the IRE1α/XBP1 pathway of the UPR and the inhibition of this pathway can inhibit growth in CARM1 expressing ovarian cancers.

ARID1A inactivation causes mitotic defects. Paradoxically, cancers with high ARID1A mutation rates typically lack copy number alterations (CNAs). Here, we show that ARID1A inactivation causes defects in telomere cohesion, which selectively eliminates gross chromosome aberrations during mitosis. ARID1A promotes the expression of cohesin subunit STAG1 that is specifically required for telomere cohesion. ARID1A inactivation causes telomere damage that can be rescued by STAG1 expression. Colony formation capability of single cells in G 2 /M, but not G 1 phase, is significantly reduced by ARID1A inactivation. This correlates with an increase in apoptosis and a reduction in tumor growth. Compared with ARID1A wild-type tumors, ARID1A -mutated tumors display significantly less CNAs across multiple cancer types. Together, these results show that ARID1A inactivation is selective against gross chromosome aberrations through causing defects in telomere cohesion, which reconciles the long-standing paradox between the role of ARID1A in maintaining mitotic integrity and the lack of genomic instability in ARID1A -mutated cancers. Cells with ARID1A mutations exhibit mitotic defects, yet show surprisingly low levels of copy number defects. Here, Zhao et al. resolve this issue by showing that ARID1A loss causes defects in telomere cohesion, which selects against gross alterations in copy number.

The Switch/Sucrose Non-fermentable (SWI/SNF) is a chromatin remodeling complex that regulates gene transcription in an ATP-dependent manner. The SWI/SNF is responsible for the regulation of many cellular processes such as the cell cycle, DNA damage repair, embryogenesis, and metabolism. Collectively, the SWI/SNF subunits are mutated in > 20% of human cancers. Furthermore, AT-Rich Interaction Domain 1A (ARID1A) is the most frequently mutated protein of the SWI/SNF in human cancers. Notably, about 50% of Ovarian Clear Cell Carcinoma (OCCC) cases possess nonsense or frameshift mutations of ARID1A causing loss of ARID1A expression. Mutational status of ARID1A has been correlated strongly to OCCC progression, and targeted therapies need development upon this premise. The works outlined throughout this thesis identify novel treatment strategies relying upon inhibition of the endoplasmic reticulum (ER) stress response. In aims I and II I describe how ARID1A mutation promotes ER stress response-mediated tumor survival via the IRE1⍺/XBP1 signaling pathway. I also show how inhibition of IRE1⍺ RNase activity selectively targets ARID1A mutant OCCC. In aim III we discuss combinatorial therapeutic approaches to treat ARID1A mutant OCCC. I identified synergy between HDAC6 inhibition and IRE1⍺ RNase inhibition or immune checkpoint blockade through anti-PDL1 immunotherapy. Together, these findings are the first to demonstrate ER stress response gene regulation by the SWI/SNF complex. These findings also establish novel therapeutic strategies for OCCC.

Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD.sup.+ metabolism influences both tissue ageing and cancer. However, the role of NAD.sup.+ metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD.sup.+ salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA-NAMPT-NAD.sup.+ signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD.sup.+-mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-[kappa]B activity. We conclude that NAD.sup.+ metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD.sup.+ augmentation should be administered with precision.