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Open Access Publications from the University of California

Scholarly Works (24 results)

  • Article
  • Peer Reviewed
UC Irvine Previously Published Works (2024)
Small cell lung cancer (SCLC) is a deadly neuroendocrine malignancy, notorious for its rapid tumor growth, early metastasis, and relatively cold immune environment. Only standard chemotherapies and a few immune checkpoint inhibitors have been approved for SCLC treatment, revealing an urgent need for novel therapeutic approaches. Moreover, SCLC has been recently recognized as a malignancy with high intratumoral and intertumoral heterogeneity, which explains the modest response rate in some patients and the early relapse. Molecular subtypes defined by the expression of lineage-specific transcription factors (ASCL1, NEUROD1, POU2F3, and, in some studies, YAP1) or immune-related genes display different degrees of neuroendocrine differentiation, immune cell infiltration, and response to treatment. Despite the complexity of this malignancy, a few biomarkers and targets have been identified and many promising drugs are currently undergoing clinical trials. In this review, we integrate the current progress on the genomic landscape of this shapeshifting malignancy, the characteristics and treatment vulnerabilities of each subtype, and promising drugs in clinical phases.
    Cover page: Landscape and Treatment Options of Shapeshifting Small Cell Lung Cancer.
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2015)
    Retinoblastoma is a pediatric tumor of the developing retina from which the genetic basis for cancer development was first described. Inactivation of both copies of the RB1 gene is the predominant initiating genetic lesion in retinoblastoma and is rate limiting for tumorigenesis. Recent whole-genome sequencing of retinoblastoma uncovered a tumor that had no coding-region mutations or focal chromosomal lesions other than in the RB1 gene, shifting the paradigm in the field. The retinoblastoma genome can be very stable; therefore, epigenetic deregulation of tumor-promoting pathways is required for tumorigenesis. This review highlights the genetic and epigenetic changes in retinoblastoma that have been reported, with special emphasis on recent whole-genome sequencing and epigenetic analyses that have identified novel candidate genes as potential therapeutic targets.
      Cover page: Genetics and Epigenetics of Human Retinoblastoma
      • Peer Reviewed
      UC Irvine Previously Published Works (2022)
        Cover page: DNA repair and epigenetics in cancer
        • Peer Reviewed
        UC Irvine Previously Published Works (2020)
          Cover page: DNA repair and epigenetic regulation in cancer
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2024)
          Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an essential protein involved in the maintenance of repressive epigenetic marks, ensuring epigenetic stability and fidelity. As an epigenetic regulator, UHRF1 comprises several functional domains (UBL, TTD, PHD, SRA, RING) that are collectively responsible for processes like DNA methylation, histone modification, and DNA repair. UHRF1 is a downstream effector of the RB/E2F pathway, which is nearly universally deregulated in cancer. Under physiological conditions, UHRF1 protein levels are cell cycle-dependent and are post-translationally regulated by proteasomal degradation. Conversely, UHRF1 is overexpressed and serves as an oncogenic driver in multiple cancers. This review focuses on the functional domains of UHRF1, highlighting its key interacting proteins and oncogenic roles in solid tumors including retinoblastoma, osteosarcoma, lung cancer, and breast cancer. Additionally, current therapeutic strategies targeting UHRF1 domains or its interactors are explored, providing an insight on potential clinical applications.
            Cover page: Oncogenic Roles of UHRF1 in Cancer.
            • Article
            • Peer Reviewed
            UC Irvine Previously Published Works (2018)
            Osteosarcoma is the most common primary bone malignancy in children and adolescents. Among the various molecular mechanisms implicated in osteosarcomagenesis, the RB-E2F pathway is of particular importance as virtually all cases of osteosarcoma display alterations in the RB-E2F pathway. In this study, we examined the transcription factor E2F family members that are associated with increased malignancy in Rb1-null osteosarcoma tumors. Using genetically engineered mouse models of osteosarcoma, we found that loss of activator E2Fs, E2F1 and E2F3, significantly delays tumor progression and increases the overall survival of the p53/Rb1-deficient osteosarcoma mouse model. We also studied the role of helicase, lymphoid specific (HELLS), a chromatin remodeling protein identified as a critical downstream effector of the RB-E2F signaling pathway in various cancers. In this study, we confirmed that the RB-E2F pathway directly regulates HELLS gene expression. We also found that HELLS mRNA is upregulated and its protein overexpressed in osteosarcoma. Using loss-of-function assays to study the role of HELLS in human osteosarcoma, we observed that HELLS has no effect on tumor proliferation and migration. Further, we pioneered the study of Hells in developmental tumor models by generating Hells conditional knockout osteosarcoma mouse models to examine the role of HELLS in osteosarcoma tumor development. We found that loss of Hells in osteosarcoma has no effect in tumor initiation and overall survival of mice. This suggests that while HELLS may serve as a biomarker for tumorigenesis and for RB-E2F pathway status, it is unlikely to serve as a relevant target for therapeutics in osteosarcoma.
              Cover page: Chromatin remodeling protein HELLS is upregulated by inactivation of the RB-E2F pathway and is nonessential for osteosarcoma tumorigenesis
              • Article
              • Peer Reviewed
              UC Irvine Previously Published Works (2024)
              Osteosarcoma (OS) is a primary malignant bone tumor with high metastasis. Poor prognosis highlights a clinical need for novel therapeutic strategies. Exosomes, also known as extracellular vesicles, have been identified as essential players in the modulation of cancer. Recent studies have suggested that OS-derived exosomes can drive pro-tumorigenic or anti-tumorigenic phenotypes by transferring specific cargos, including proteins, nucleic acids, and metabolites, to neighboring cells, significantly impacting the regulation of cellular processes. This review discusses the advancement of exosomes and their cargos in OS. We examine how these exosomes contribute to the modulation of cellular phenotypes associated with tumor progression and metastasis. Furthermore, we explore the potential of exosomes as valuable biomarkers for diagnostics and prognostic purposes and their role in shaping innovative therapeutic strategies in OS treatment development.
                Cover page: Exploring the Impact of Exosomal Cargos on Osteosarcoma Progression: Insights into Therapeutic Potential
                • Thesis
                • Peer Reviewed
                UC Irvine Electronic Theses and Dissertations (2019)

                ABSTRACT OF THE DISSERTATION

                Elucidating the mechanism through which loss-of-function in RB1 mediates poor prognosis in osteosarcoma

                By

                Stephanie Cherie Wu

                Doctor of Philosophy in Biological Sciences

                University of California, Irvine, 2019

                Assistant Professor Claudia A. Benavente, Chair

                Osteosarcoma is the most common primary bone malignancy in children and adolescents. Among the various molecular mechanisms implicated in osteosarcomagenesis reviewed in Chapter 1, the RB/E2F pathway is of particular importance as virtually all cases of osteosarcoma display alterations in the this signaling pathway. Loss of function mutations at the retinoblastoma (RB1) gene are associated with increased mortality, metastasis and poor therapeutic outlook in osteosarcoma. However, the mechanism(s) through which loss of RB worsens clinical outcome remain to be elucidated. We examined the transcription factor E2F family members that are associated with increased malignancy in RB-null osteosarcoma tumors and found that loss of activator E2Fs, E2F1 and E2F3, significantly delays tumor progression and increases the overall survival of the Tp53/Rb1-deficient osteosarcoma mouse model (Chapter 2). We then studied the role of two critical downstream effectors of the RB/E2F pathway, HELLS and UHRF1. While both are upregulated and overexpressed in osteosarcoma, we observed that HELLS has limited effect on tumor proliferation and migration. Loss of Hells in osteosarcoma has no effect in tumor initiation and overall survival of osteosarcoma mice. This suggests that while HELLS may serve as a biomarker for tumorigenesis and for RB/E2F pathway status, it is unlikely to serve as a relevant target for therapeutics in osteosarcoma (Chapter 3). On the contrary, we showed that UHRF1 upregulation is critical in rendering osteosarcoma cells more aggressive. Using gain/loss-of-function assays to study the role of UHRF1 in osteosarcoma, we observed that UHRF1 is involved in promoting cell proliferation, migration, and invasion. Loss of Uhrf1 in genetically engineered osteosarcoma model lengthens the life span of mice bearing osteosarcoma and decreases pulmonary metastases. These are described in chapter 4, where we discuss how UHRF1 mediates its tumor-promoting functions in osteosarcoma, and provide evidence supporting UHRF1 targeting as a novel therapeutic option. Taken together, this study illuminates new mechanistic insights of RB-mediated poor prognosis that could improve current therapeutic strategies of osteosarcoma, as well as other malignancies harboring RB/E2F pathway inactivation. Following our discovery, chapter 5 documents our proposed methods in attempting to provide a more comprehensive mechanistic understanding of the RB-UHRF1 network.

                  Cover page: Elucidating the mechanism through which loss-of-function in RB1 mediates poor prognosis in osteosarcoma
                  • Article
                  • Peer Reviewed
                  UC Irvine Previously Published Works (2020)
                    Cover page: Heavenly HELLS? A potential new therapeutic target for retinoblastoma
                    • Article
                    • Peer Reviewed
                    UC Irvine Previously Published Works (2012)
                    Sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs), NAD(+)-dependent enzymes, link cellular energy status with responses to environmental stresses. Skin is frequently exposed to the DNA damaging effects of UV irradiation, a known etiology in skin cancer. Thus, understanding the defense mechanisms in response to UV, including the role of SIRTs and PARPs, may be important in developing skin cancer prevention strategies. Here, we report expression of the seven SIRT family members in human skin. SIRTs gene expressions are progressively upregulated in A431 epidermoid carcinoma cells (SIRTs1 and 3), actinic keratoses (SIRTs 2, 3, 5, 6, and 7) and squamous cell carcinoma (SIRTs 1-7). Photodamage induces dynamic changes in SIRT expression with upregulation of both SIRT1 and SIRT4 mRNAs. Specific losses of SIRT proteins occur early after photodamage followed by accumulation later, especially for SIRT4. Niacin restriction, which decreases NAD(+), the sirtuin substrate, results in an increase in acetylated proteins, upregulation of SIRTs 2 and 4, increased inherent DNA damage, alterations in SIRT responses to photodamage, abrogation of PARP activation following photodamage, and increased sensitivity to photodamage that is completely reversed by repleting niacin. These data support the hypothesis that SIRTs and PARPs play important roles in resistance to photodamage and identify specific SIRTs that respond to photodamage and may be targets for skin cancer prevention.
                      Cover page: Effects of Niacin Restriction on Sirtuin and PARP Responses to Photodamage in Human Skin
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