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Chromatin structure regulates cancer-specific alternative splicing events in primary HPV-related oropharyngeal squamous cell carcinoma.

ABSTRACT: Human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV+ OPSCC) represents a unique disease entity within head and neck cancer with rising incidence. Previous work has shown that alternative splicing events (ASEs) are prevalent in HPV+ OPSCC, but further validation is needed to understand the regulation of this process and its role in these tumours. In this study, eleven ASEs (GIT2, CTNNB1, MKNK2, MRPL33, SIPA1L3, SNHG6, SYCP2, TPRG1, ZHX2, ZNF331, and ELOVL1) were selected for validation from 109 previously published candidate ASEs to elucidate the post-transcriptional mechanisms of oncogenesis in HPV+ disease. In vitro qRT-PCR confirmed differential expression of 9 of 11 ASE candidates, and in silico analysis within the TCGA cohort confirmed 8 of 11 candidates. Six ASEs (MRPL33, SIPA1L3, SNHG6, TPRG1, ZHX2, and ELOVL1) showed significant differential expression across both methods. Further evaluation of chromatin modification revealed that ASEs strongly correlated with cancer-specific distribution of acetylated lysine 27 of histone 3 (H3K27ac). Subsequent epigenetic treatment of HPV+ HNSCC cell lines (UM-SCC-047 and UPCI-SCC-090) with JQ1 not only induced downregulation of cancer-specific ASE isoforms, but also growth inhibition in both cell lines. The UPCI-SCC-090 cell line, with greater ASE expression, also showed more significant growth inhibition after JQ1 treatment. This study confirms several novel cancer-specific ASEs in HPV+OPSCC and provides evidence for the role of chromatin modifications in regulation of alternative splicing in HPV+OPSCC. This highlights the role of epigenetic changes in the oncogenesis of HPV+OPSCC, which represents a unique, unexplored target for therapeutics that can alter the global post-transcriptional landscape.

SUBMITTER: Guo T

PROVIDER: S-EPMC7518675 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Chromatin structure regulates cancer-specific alternative splicing events in primary HPV-related oropharyngeal squamous cell carcinoma.

Guo Theresa T Zambo Kristina Diana A KDA Zamuner Fernando T FT Ou Tingting T Hopkins Christopher C Kelley Dylan Z DZ Wulf Hildegard A HA Winkler Eli E Erbe Rossin R Danilova Ludmila L Considine Michael M Sidransky David D Favorov Alexander A Florea Liliana L Fertig Elana J EJ Gaykalova Daria A DA

Epigenetics 20200322 9

Human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV+ OPSCC) represents a unique disease entity within head and neck cancer with rising incidence. Previous work has shown that alternative splicing events (ASEs) are prevalent in HPV+ OPSCC, but further validation is needed to understand the regulation of this process and its role in these tumours. In this study, eleven ASEs (<i>GIT2, CTNNB1, MKNK2, MRPL33, SIPA1L3, SNHG6, SYCP2, TPRG1, ZHX2, ZNF331</i>, and <i>ELOVL1)</i> were ...[more]

PMID: 32164487

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Project description:The global rise of HPV(+) oropharyngeal squamous cell carcinoma (OPSCC) has generated considerable interest underlying its etiology and management. Despite an overall decline in head and neck malignancies, the incidence in OPSCC has by contrast sharply risen, with HPV(+) subtypes now comprising 80% of all OPSCC.1,2 Relative to HPV(-) OPSCC, HPV(+) patients are more responsive to chemoradiation and harbor a 52% risk-of-death reduction.3 Despite this distinct outcome, treatment regimens remain the same for all OPSCC subtypes (smoking-driven and virus-driven), rather than an adaptive approach to what most consider distinct diseases. The short-term effects (e.g., mucositis, odynophagia) and long-term toxicities (e.g., xerostomia, dysphagia, ototoxicity) from treatment substantially affect quality of life, and rival the impact of the cancer itself. Recently published as well as ongoing trials are actively examining deintensification approaches2,4-9, with the goal of diminishing treatment sequelae for HPV(+) subtypes. While deintensification may decrease chemoradiation-related toxicities, it nonetheless may also undertreat a meaningful percentage of HPV(+) patients who may then recur. In examining national trials, 19% of HPV(+) patients had disease progression after therapy, with a two-year survival rate of 60%.10 Current methods to ascertain HPV status involve p16 staining. However, on comparison with gold standard E6/E7 expression by qPCR, p16 harbored a 15% false positivity rate11, suggesting limited utility as a sole biomarker for deintensification. Improved molecular stratification would greatly enhance the clinician’s ability to precisely tailor treatment while minimizing the risk of jeopardizing outcomes. One approach encompasses in-depth proteomic profiling of HPV(+) OPSCC to reveal distinct protein expression profiles and delineate clinically relevant upstream pathways. In turn, these proteomic differences may distinguish higher-risk disease (cases predisposed to recurrence that may benefit from treatment intensification) from lower-risk phenotypes (cases whose treatment response is sufficiently robust to warrant deintensification). Here, two HPV(+) OPSCC cohorts stratified by treatment response are compared via a hybrid data dependent acquisition/data independent acquisition (DDA/DIA) approach via mass spectrometry. We focused on detection of low-abundance proteins to highlight proteomic signatures that can be potentially exploited for treatment stratification.

Dataset Information

Chromatin structure regulates cancer-specific alternative splicing events in primary HPV-related oropharyngeal squamous cell carcinoma.

Publications

Chromatin structure regulates cancer-specific alternative splicing events in primary HPV-related oropharyngeal squamous cell carcinoma.

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