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Open Access Publications from the University of California

Scholarly Works (10 results)

  • Article
  • Peer Reviewed
UCLA Previously Published Works (2016)
Chemoresistance is a major barrier to effective chemotherapy of solid tumors, including head and neck squamous cell carcinoma (HNSCC). Recently, autophagy, a highly conservative intracellular recycling system, has shown to be associated with chemoresistance in cancer cells. However, little is known about how autophagy plays a role in the development of chemoresistance in HNSCC and how autophagy is initiated when HNSCC cells undergo cytotoxic stress. Here, we report that autophagy was activated when HNSCC cells are treated with the proteasome inhibitor bortezomib, proposed as an alternative chemotherapeutic agent for both primary and cisplatin-resistant HNSCC cells. Ablation of histone deacetylase 6 (HDAC6) expression and its activity in HNSCC cells significantly inhibited autophagy induction by altering the phosphorylation status of mammalian target of rapamycin and enhanced the bortezomib cytotoxicity. Similarly, a combination regimen of bortezomib and the histone deacetylase inhibitor trichostatin A abolished HDAC6 activity and decreased autophagy induction while significantly enhancing bortezomib-induced apoptosis in HNSCC cells. These data uncover a novel molecular mechanism indicating that HDAC6 may serve as a critical causal link between autophagy, apoptosis, and the cell survival response in HNSCC. A combination regimen resulting in regression of autophagy improves chemotherapeutic efficacy, thereby providing a new strategy to overcome chemoresistance and to improve the treatment and survival of HNSCC patients.
    Cover page: Inhibition of HDAC6 Protein Enhances Bortezomib-induced Apoptosis in Head and Neck Squamous Cell Carcinoma (HNSCC) by Reducing Autophagy*
    • Thesis
    • Peer Reviewed
    UCLA Electronic Theses and Dissertations (2017)

    Development of chemoresistance, invasive growth, and metastasis remain key challenges in head and neck squamous cell carcinoma (HNSCC) therapy. Recent studies revealed that an activated hepatocyte growth factor receptor (MET) is frequently overexpressed and highly associated with HNSCC invasion and metastasis. Also, autophagy, a highly conservative intracellular recycling system, has shown to play a primary role in cancer cells to attenuate cytotoxicity of chemoreagents in many hematopoietic and solid cancers. However, little is known about the epigenetic regulation of the MET signaling pathway or autophagy induction and whether it plays a role in promoting HNSCC invasion and metastasis or development of resistance to therapy. In our study, we found that histone deacetylase 6 (HDAC6) is a key epigenetic regulator of autophagy that promotes chemoresistance in HNSCC against the proteasome inhibitor, Bortezomib. The depletion of HDAC6 inhibited autophagy activation and enhanced Bortezomib-induced apoptosis in HNSCC cells. Mechanistically, we revealed that HDAC6 mediated activation of autophagy by modulating activation of protein kinases such as unc-51 like autophagy activating kinase 1 (ULK1) to promote clearing of large quantities of cytotoxic, unfolded protein aggregates induced by the Bortezomib. In addition, we found histone demethylases KDM6B plays an important role in acquiring cisplatin resistance in HNSCC and in unraveling the mechanism associated with the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Interestingly, we also identified KDM6B as an essential epigenetic regulator of MET-driven HNSCC metastasis. KDM6B was highly expressed in both the growth factor-induced HNSCC cells and in cells overexpressing the oncogenic translocated promoter region MET (TPR-MET). KDM6B knockdown significantly decreased the HNSCC invasion and metastasis by regulating the expression of ETS proto-oncogene 1 (ETS1) and the high mobility group AT-Hook 2 (HMGA2) genes, known as the drivers of metastasis. Mechanistically, KDM6B facilitated the binding of the transcription factor ELK1, a downstream target of c-MET signaling pathway, to the promoters of ETS1 and HMGA2. In conclusion, our study provides insight into the epigenetic regulation of HNSCC chemoresistance, invasion, and metastasis and suggests that HDAC6 and KDM6B could be an important therapeutic target to improve chemotherapeutic efficacy and to decrease the tumor burden of HNSCC patients.

      Cover page: Epigenetic Regulation of Head and Neck Squamous Cell Carcinoma Chemoresistance, Invasion, and Metastasis
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2022)
      Aging of craniofacial skeleton significantly impairs the repair and regeneration of trauma-induced bony defects, and complicates dental treatment outcomes. Age-related alveolar bone loss could be attributed to decreased progenitor pool through senescence, imbalance in bone metabolism and bone-fat ratio. Mesenchymal stem cells isolated from oral bones (OMSCs) have distinct lineage propensities and characteristics compared to MSCs from long bones, and are more suited for craniofacial regeneration. However, the effect of epigenetic modifications regulating OMSC differentiation and senescence in aging has not yet been investigated. In this study, we found that the histone demethylase KDM4B plays an essential role in regulating the osteogenesis of OMSCs and oral bone aging. Loss of KDM4B in OMSCs leads to inhibition of osteogenesis. Moreover, KDM4B loss promoted adipogenesis and OMSC senescence which further impairs bone-fat balance in the mandible. Together, our data suggest that KDM4B may underpin the molecular mechanisms of OMSC fate determination and alveolar bone homeostasis in skeletal aging, and present as a promising therapeutic target for addressing craniofacial skeletal defects associated with age-related deteriorations.
        Cover page: Loss of KDM4B impairs osteogenic differentiation of OMSCs and promotes oral bone aging
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2024)
        mEAK-7 (mammalian EAK-7 or MTOR-associated protein, eak-7 homolog), is an evolutionarily conserved lysosomal membrane protein that is highly expressed in several cancer cells. Multiple recent studies have identified mEAK-7 as a positive activator of mTOR (mammalian/mechanistic target of rapamycin) signaling via an alternative mTOR complex, implying that mEAK-7 plays an important role in the promotion of cancer proliferation and migration. In addition, structural analyses investigating interactions between mEAK-7 and V-ATPase, a protein complex responsible for regulating pH homeostasis in cellular compartments, have suggested that mEAK-7 may contribute to V-ATPase-mediated mTORC1 activation. The C-terminal α-helix of mEAK-7 binds to the D and B subunits of the V-ATPase, creating a pincer-like grip around its B subunit. This binding undergoes partial disruption during ATP hydrolysis, potentially enabling other proteins such as mTOR to bind to the α-helix of mEAK-7. mEAK-7 also promotes chemoresistance and radiation resistance by sustaining DNA damage-mediated mTOR signaling through interactions with DNA-PKcs (DNA-dependent protein kinase catalytic subunit). Taken together, these findings indicate that mEAK-7 may be a promising therapeutic target against tumors. However, the precise molecular mechanisms and signal transduction pathways of mEAK-7 in cancer remain largely unknown, motivating the need for further investigation. Here, we summarize the current known roles of mEAK-7 in normal physiology and cancer development by reviewing the latest studies and discuss potential future developments of mEAK-7 in targeted cancer therapy.
          Cover page: Targeting of lysosomal-bound protein mEAK-7 for cancer therapy.
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2021)
          Developing strategies to activate tumor-cell-intrinsic immune response is critical for improving tumor immunotherapy by exploiting tumor vulnerability. KDM4A, as a histone H3 lysine 9 trimethylation (H3K9me3) demethylase, has been found to play a critical role in squamous cell carcinoma (SCC) growth and metastasis. Here we report that KDM4A inhibition promoted heterochromatin compaction and induced DNA replication stress, which elicited antitumor immunity in SCC. Mechanistically, KDM4A inhibition promoted the formation of liquid-like HP1γ puncta on heterochromatin and stall DNA replication, which activated tumor-cell-intrinsic cGAS-STING signaling through replication-stress-induced cytosolic DNA accumulation. Moreover, KDM4A inhibition collaborated with PD1 blockade to inhibit SCC growth and metastasis by recruiting and activating CD8+ T cells. In vivo lineage tracing demonstrated that KDM4A inhibition plus PD1 blockade efficiently eliminated cancer stem cells. Altogether, our results demonstrate that targeting KDM4A can activate anti-tumor immunity and enable PD1 blockade immunotherapy by aggravating replication stress in SCC cells.
            Cover page: Targeting KDM4A epigenetically activates tumor-cell-intrinsic immunity by inducing DNA replication stress
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2024)
            Abstract: Exosomes derived from mesenchymal stem cells are an active area of research due to their therapeutic potential in treating osteoporosis. To further harness their therapeutic performance in modulating bone resorption, equipped exosomes with osteoclast‐targeting moieties on their surface as well as chemokine receptor antagonists blocking osteoclast recruitment. Phosphatidylserine (PS), a membrane lipid exerting immunosuppressive and phagocytic signals, is incorporated in the membrane of exosome mimetics (EMs) to achieve a marked affinity for osteoclast precursors and potential anti‐resorptive effects. This is also aimed to tackle a CXCL9‐CXCR3 ligand‐receptor axis, a critical signaling axis in regulating osteoclast precursor recruitment and differentiation at bone resorption sites, by encapsulating a chemical antagonist of CXCR3, AMG487, in the PS‐incorporated EMs (PS‐EMs). The osteoclast‐targeting PS‐EMs loaded with AMG487 effectively protected against bone loss in an ovariectomized mouse model. These findings demonstrate the great promise of PS‐EMs as anti‐resorptive nanotherapies for alleviating osteoporosis.
              Cover page: Phosphatidylserine‐Incorporated Exosome Mimetics Encapsulating CXCR3 Antagonist Alleviate OsteoporosisCreative Commons 'BY-NC-ND' version 4.0 license
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2023)
              Growing evidence suggests an association between Mycoplasma infections and the development and progression of prostate cancer (PCa). In this study, we report that chronic and persistent M. hyorhinis infection induced robust TNF-α secretion from PCa cells. TNF-α secreted from M. hyorhinis-infected PCa cells subsequently led to activation of the NF-κB pathway. Chronic M. hyorhinis infection induced gene expression of pro-inflammatory cytokines and chemokines in a NF-κB-dependent manner and promoted cell proliferation, migration, and invasion in PCa cells. The elimination of M. hyorhinis in PCa cells significantly blocked TNF-α secretion, gene expression of cytokines and chemokines, migration, and invasion in PCa cells, suggesting M. hyorhinis-induced TNF-α plays an important role to promote malignant transformation of PCa. Furthermore, second mitochondria-derived activator of caspases (SMAC) mimetics potentiated caspase activation and cell death in M. hyorhinis-infected PCa by antagonizing inhibitor of apoptosis proteins (IAPs) activity. Tissue microarray analysis indicated that TNF-α is co-expressed in M. hyorhinis-infected human patient tissues. Findings from this study advance our understanding of the mycoplasma-oncogenesis process and suggest the potential for new approaches for preventions, diagnosis, and therapeutic approaches against prostate cancers.
                Cover page: Mycoplasma hyorhinis infection promotes TNF-α signaling and SMAC mimetic-mediated apoptosis in human prostate cancer
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2023)

                Introduction

                The regeneration of pulp tissue is crucial for true regenerative endodontic treatment, which requires a reduction in osteogenic differentiation. Garcinol, a histone acetyltransferase inhibitor, is a natural regulator that is known to suppress the osteogenic differentiation of dental pulp stem cells. In this study, the inhibitory effect of garcinol on the osteogenic differentiation of human dental pulp stem cells (hDPSCs) was evaluated using three-dimensional culture under in vitro and in vivo conditions.

                Methods

                hDPSCs were obtained from caries-free third molars and cultured with 10 μM garcinol for 7 days in an ultra-low attachment plate. The cell stemness and expression of osteogenic differentiation-related genes were analyzed using reverse transcription-polymerase chain reaction and single-cell analysis. A transplantation experiment was performed in mice to investigate whether garcinol-treated hDPSCs showed restrained osteogenic differentiation.

                Results

                hDPSCs cultured in the U-shaped ultra-low attachment plate showed the highest expression of stemness-related genes. Garcinol-treated hDPSCs demonstrated downregulation of osteogenic differentiation, with lower expression of bone sialoprotein, which is related to bone formation, and higher expression of dentin sialophosphoprotein, which is related to dentin formation. However, the garcinol-treated hDPSCs did not show any alterations in their stemness. Consistent results were observed in the transplantation experiment in mice.

                Conclusions

                Garcinol reduced the osteogenic differentiation of hDPSCs, which can contribute to true regenerative endodontic treatment.
                  Cover page: Biological Function and Potential Applications of Garcinol in Human Dental Pulp Stem Cells
                  • Article
                  • Peer Reviewed
                  UCLA Previously Published Works (2024)
                  This study evaluated 10-year secular changes in dental maturity and dental development among Korean children. A retrospective analysis of panoramic radiograph samples from Korean children (4–16 years old) taken in 2010 and 2020 was conducted. The 2010 group consisted of 3491 radiographs (1970 boys and 1521 girls), and the 2020 group included 5133 radiographs (2825 boys and 2308 girls). Using Demirjian’s method, dental maturity scores and dental developmental stages were assessed. For intra-observer reliability, Weighted Cohen’s kappa was used, and Mann-Whitney U tests were performed to compare the 2020 and 2010 groups. A slight acceleration in dental maturity was observed in both boys and girls, with the difference being more noticeable in boys at an earlier age. Statistically significant differences were noted at ages 4, 5 and 7 for boys, and at age 6 for girls. Despite these differences, the individual dental development stages of 2020 and 2010 showed inconsistent trends with limited differences. Generally, girls demonstrate more advanced dental maturity than boys. A slight acceleration in Korean children’s dental maturity was observed over a 10-year period when comparing the 2020 groups to the 2010 groups.
                    Cover page: Secular changes in dental development of Korean children aged 4 to 16 years over a 10-year periodCreative Commons 'BY-NC-ND' version 4.0 license
                    • Article
                    • Peer Reviewed
                    UCLA Previously Published Works (2017)
                    Squamous cell carcinoma in the head and neck (HNSCC) is a common yet poorly understood cancer, with adverse clinical outcomes due to treatment resistance, recurrence, and metastasis. Putative cancer stem cells (CSCs) have been identified in HNSCC, and BMI1 expression has been linked to these phenotypes, but optimal treatment strategies to overcome chemotherapeutic resistance and eliminate metastases have not yet been identified. Here we show through lineage tracing and genetic ablation that BMI1+ CSCs mediate invasive growth and cervical lymph node metastasis in a mouse model of HNSCC. This model and primary human HNSCC samples contain highly tumorigenic, invasive, and cisplatin-resistant BMI1+ CSCs, which exhibit increased AP-1 activity that drives invasive growth and metastasis of HNSCC. Inhibiting AP-1 or BMI1 sensitized tumors to cisplatin-based chemotherapy, and it eliminated lymph node metastases by targeting CSCs and the tumor bulk, suggesting potential regimens to overcome resistance to treatments and eradicate HNSCC metastasis.
                      Cover page: Targeting BMI1+ Cancer Stem Cells Overcomes Chemoresistance and Inhibits Metastases in Squamous Cell Carcinoma
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