Selective regulation of tuft cell-like small cell lung cancer by novel transcriptional co-activators C11orf53 and COLCA2.
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ABSTRACT:
SUBMITTER: Zhou C
PROVIDER: S-EPMC9576728 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
Publications
Selective regulation of tuft cell-like small cell lung cancer by novel transcriptional co-activators C11orf53 and COLCA2.
Zhou Chen C Huang Hui H Wang Yunyi Y Sendinc Erdem E Shi Yang Y
Cell discovery 20221018 1
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Project description:The DepMap project has generated a huge resource for investigating selectively essential genes, which represent potential cancer therapeutic targets. However, manually sorting out which of the hundreds of selectively essential genes is understudied and warrants investigations is time-consuming and probably not practical. To efficiently identify uncharacterized, selectively essential genes, we collected and ranked the 347 selectively essential genes from the DepMap dataset by their PubMed publication counts, based on the assumption that genes with low publication counts are un-studied or under-studied. We successfully validated two of the top candidates in our ranking system, C11orf53 and COLCA2, as new vulnerabilities that are selectively essential in the class II POU domain transcription factor POU2F3-dependent tuft cell-like small cell lung cancer (SCLC) cell lines. Importantly, we found that the sequence motif, which mediates physical interactions of the transcriptional co-activator POU2AF1 with two of the class II POU domain-containing family of transcription factors (POU2F1 and POU2F2), is also present in the N-terminal regions of C11orf53 and COLCA2. We further confirmed that 1) COLCA2 physically interacts with POU2F3 through this conserved sequence motif; 2) this interaction is important for COLCA2 to regulate tuft cell-like SCLC cell growth, and 3) both C11orf53 and COLCA2 contain transcriptional co-activator domains. Consistently, we find similar transcriptomic changes in response to the loss of COLCA2 or POU2F3 in SCLC cells. In summary, our analysis pipeline enables identification and prioritization of understudied but important, selectively essential genes, leading to the identification of two new transcriptional co-activators for the class II POU domain transcription factors. Disruption of this important physical interaction is predicted to be a potential therapeutic strategy to selectively inhibit tuft cell-like SCLCs.
2022-10-18 | GSE212912 | GEO
Project description:Selective Regulation of Tuft Cell-Like Small Cell Lung Cancer by Novel Transcriptional Co-activators C11orf53 and COLCA2
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Project description:Small cell lung cancer (SCLC) is widely considered to be a tumor of pulmonary neuroendocrine cells; however, a variant form of this disease has been described that lacks neuroendocrine features. Here, we applied domain-focused CRISPR screening to human cancer cell lines to identify the transcription factor (TF) POU2F3 (POU class 2 homeobox 3; also known as SKN-1a/OCT-11) as a powerful dependency in a subset of SCLC lines. An analysis of human SCLC specimens revealed that POU2F3 is expressed exclusively in variant SCLC tumors that lack expression of neuroendocrine markers and instead express markers of a chemosensory lineage known as tuft cells. Using chromatin- and RNA-profiling experiments, we provide evidence that POU2F3 is a master regulator of tuft cell identity in a variant form of SCLC. Moreover, we show that most SCLC tumors can be classified into one of three lineages based on the expression of POU2F3, ASCL1, or NEUROD1. Our CRISPR screens exposed other unique dependencies in POU2F3-expressing SCLC lines, including the lineage TFs SOX9 and ASCL2 and the receptor tyrosine kinase IGF1R (insulin-like growth factor 1 receptor). These data reveal POU2F3 as a cell identity determinant and a dependency in a tuft cell-like variant of SCLC, which may reflect a previously unrecognized cell of origin or a trans-differentiation event in this disease.
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