RESUMEN
The most aggressive subtype of medulloblastoma (MB), Group 3, is characterized by MYC amplifications. However, targeting MYC has proven unsuccessful, and there remains a lack of therapeutic targets for treating MB. Studies have shown that the B7 homolog 3 (B7H3) promotes cell proliferation and tumor cell invasion in a variety of cancers. Similarly, it was recently revealed that B7H3 promotes angiogenesis in Group 3 MB and likely facilitates MB metastasis through exosome biogenesis. While therapies targeting B7H3 remain in the early stages of development, targeting upstream regulators of B7H3 expression may be more effective for halting MB progression. Notably, MYC and the enhancer of zeste homolog 2 (EZH2) are known to regulate B7H3 expression, and a previous study by the authors suggested that B7H3 amplifications present in MB are likely the result of EZH2MYC mediated activities. In the present study, it was reported that overexpression of EZH2 is associated with lower overall survival in Group 3 MB patients. It was also revealed that inhibition of EZH2 significantly reduces B7H3 and MYC transcript levels and upregulates miR29a, indicating that EZH2 posttranscriptionally regulates B7H3 expression in Group 3 MB cells. Pharmacological inhibition of EZH2 using EPZ005687 attenuated MB cell viability and reduced the expression of B7H3. Similarly, pharmacological inhibition and knockdown of EZH2 led to the downregulation of MYC, B7H3, and H3K27me3. Further, EZH2 silencing induced apoptosis and reduced colonyforming ability in MB cells, whereas EZH2 inhibition in MYCamplified C17.2 neural stem cells induced G2/M phase arrest while downregulating B7H3 expression. Collectively, the current study positions EZH2 as a viable target for the future development of MB treatments and that targeting EZH2 in combination with B7H3 immunotherapy may be an effective treatment for halting MB progression.
Asunto(s)
Neoplasias Cerebelosas , Meduloblastoma , Humanos , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Meduloblastoma/genética , Meduloblastoma/metabolismo , Línea Celular Tumoral , Factores de Transcripción/metabolismo , Proliferación Celular , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/metabolismoRESUMEN
INTRODUCTION: Oftentimes, radiation therapy (RT) is ineffective due to the development of radioresistance (RR). However, studies have shown that targeting epigenetic modifiers to enhance radiosensitivity represents a promising direction of clinical investigation. AREAS COVERED: This review discusses the mechanisms by which epigenetic modifiers alter radiosensitivity through dysregulation of MAPK-ERK and AKT-mTOR signaling. Finally, we discuss the clinical directions for targeting epigenetic modifiers and current radiology techniques used in the clinic.We searched PubMed and ScienceDirect databases from April 4th, 2022 to October 18th, 2022. We examined 226 papers related to radioresistance, epigenetics, MAPK, and PI3K/AKT/mTOR signaling. 194 papers were selected for this review. Keywords used for this search include, 'radioresistance,' 'radiosensitivity,' 'radiation,' 'radiotherapy,' 'particle radiation,' 'photon radiation,' 'epigenetic modifiers,' 'MAPK,' 'AKT,' 'mTOR,' 'cancer,' and 'PI3K.' We examined 41 papers related to clinical trials on the aforementioned topics. Outcomes of interest were safety, overall survival (OS), dose-limiting toxicities (DLT), progression-free survival (PFS), and maximum tolerated dose (MTD). EXPERT OPINION: Current studies focusing on epigenetic mechanisms of RR strongly support the use of targeting epigenetic modifiers as adjuvants to standard cancer therapies. To further the success of such treatments and their clinical benefit , both preclinical and clinical studies are needed to broaden the scope of known radioresistant mechanisms.
Asunto(s)
Neoplasias , Proteínas Proto-Oncogénicas c-akt , Humanos , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Epigénesis Genética , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias/genética , Neoplasias/radioterapia , Línea Celular TumoralRESUMEN
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Maximum safe resection, postoperative craniospinal irradiation, and chemotherapy are the standard of care for MB patients. MB is classified into four subgroups: Shh, Wnt, Group 3, and Group 4. Of these subgroups, patients with Myc+ Group 3 MB have the worst prognosis, necessitating alternative therapies. There is increasing interest in targeting epigenetic modifiers for treating pediatric cancers, including MB. Using an RNAi functional genomic screen, we identified the lysine methyltransferase SMYD3, as a crucial epigenetic regulator that drives the growth of Group 3 Myc+ MB cells. We demonstrated that SMYD3 directly binds to the cyclin D3 promoter to activate its transcription. Further, SMYD3 depletion significantly reduced MB cell proliferation and led to the downregulation of cyclin D3, cyclin D1, pRBSer795, with concomitant upregulations in RB in vitro. Similar results were obtained following pharmacological inhibition of SMYD3 using BCI-121 ex vivo. SMYD3 knockdown also promoted cyclin D1 ubiquitination, indicating that SMYD3 plays a vital role in stabilizing the cyclin D1 protein. Collectively, our studies demonstrate that SMYD3 drives cell cycle progression in Group 3 Myc+ MB cells and that targeting SMYD3 has the potential to improve clinical outcomes for high-risk patients.