Abstract
Rationale: The current molecular classification of small-cell lung cancer (SCLC) on the basis of the expression of four lineage transcription factors still leaves its major subtype SCLC-A as a heterogeneous group, necessitating more precise characterization of lineage subclasses. Objectives: To refine the current SCLC classification with epigenomic profiles and to identify features of the redefined SCLC subtypes. Methods: We performed unsupervised clustering of epigenomic profiles on 25 SCLC cell lines. Functional significance of NKX2-1 (NK2 homeobox 1) was evaluated by cell growth, apoptosis, and xenograft using clustered regularly interspaced short palindromic repeats–Cas9 (CRISPR-associated protein 9)–mediated deletion. NKX2-1–specific cistromic profiles were determined using chromatin immunoprecipitation followed by sequencing, and its functional transcriptional partners were determined using coimmunoprecipitation followed by mass spectrometry. Rb1flox/flox; Trp53flox/flox and Rb1flox/flox; Trp53flox/flox; Nkx2-1flox/flox mouse models were engineered to explore the function of Nkx2-1 in SCLC tumorigenesis. Epigenomic landscapes of six human SCLC specimens and 20 tumors from two mouse models were characterized. Measurements and Main Results: We identified two epigenomic subclusters of the major SCLC-A subtype: SCLC-Aa and SCLC-As. SCLC-Aa was characterized by the presence of a super-enhancer at the NKX2-1 locus, which was observed in human SCLC specimens and a murine SCLC model. We found that NKX2-1, a dual lung and neural lineage factor, is uniquely relevant in SCLC-Aa. In addition, we found that maintenance of this neural identity in SCLC-Aa is mediated by collaborative transcriptional activity with another neuronal transcriptional factor, SOX1 (SRY-box transcription factor 1). Conclusions: We comprehensively describe additional epigenomic heterogeneity of the major SCLC-A subtype and define the SCLC-Aa subtype by the core regulatory circuitry of NKX2-1 and SOX1 super-enhancers and their functional collaborations to maintain neuronal linage state.
Original language | English |
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Pages (from-to) | 1480-1494 |
Number of pages | 15 |
Journal | American Journal of Respiratory and Critical Care Medicine |
Volume | 206 |
Issue number | 12 |
DOIs | |
State | Published - 15 Dec 2022 |
Keywords
- NKX2-1/TTF-1
- SCLC
- SOX1
- small-cell lung cancer
- superenhancer