PPAPDC1B and WHSC1L1 Are Common Drivers of the 8p11-12 Amplicon, Not Only in Breast Tumors But Also in Pancreatic Adenocarcinomas and Lung Tumors

Abstract

Amplification of the 8p11-12 chromosomal region is a common genetic event in many epithelial cancers. In breast cancer, several genes within this region have been shown to display oncogenic activity. Among these genes, the enzyme-encoding genes, PPAPDC1B and WHSC1L1, have been identified as potential therapeutic targets. We investigated whether PPAPDC1B and WHSC1L1 acted as general driver genes, thereby serving as therapeutic targets in other tumors with 8p11-12 amplification. By using publicly available genomic data from a panel of 883 cell lines derived from different cancers, we identified the cell lines presenting amplification of both WHSC1L1 and PPAPDC1B. In particular, we focused on cell lines derived from lung cancer and pancreatic adenocarcinoma and found a correlation between the amplification of PPAPDC1B and WHSC1L1 with their overexpression. Loss-of-function studies based on the use of siRNA and shRNA demonstrated that PPAPDC1B and WHSC1L1 played a major role in regulating the survival of pancreatic adenocarcinoma and small-cell lung cancer-derived cell lines, both in anchorage-dependent and anchorage-independent conditions, displaying amplification and overexpression of these genes. We also demonstrated that PPAPDC1B and WHSC1L1 regulated xenograft growth in these cell lines. Finally, quantitative RT-PCR experiments after PPAPDC1B and WHSC1L1 knockdown revealed exclusive PPAPDC1B and WHSC1L1 gene targets in small-cell lung cancer and pancreatic adenocarcinoma-derived cell lines compared with breast cancer.

Mining the Plasma Cell Transcriptome for Novel Cell Surface Proteins

“…PLPP5 is estimated to be amplified in 10–15% of ductal breast carcinomas, and its knock-down in breast cancer cell lines causes an increase in apoptosis [24,25]. Similar observations have also been reported in pancreatic adenocarcinoma and small-cell lung cancer cell lines [25]. Within the mouse immune system we found that Plpp5 expression was highly restricted to ASCs.…”

“…Although the function of PLPP5 has not been determined, it has been proposed to have an oncogenic role in breast cancer. PLPP5 is estimated to be amplified in 10–15% of ductal breast carcinomas, and its knock-down in breast cancer cell lines causes an increase in apoptosis [24,25]. Similar observations have also been reported in pancreatic adenocarcinoma and small-cell lung cancer cell lines [25].…”

Mutation Spectra of Histone Methyltransferases With Canonical SET Domains and EZH2-Targeted Therapy

“…The SETD1B gene is amplified in prostate cancer [33] and the ASH1L, SETD1A and SUV420H1 genes on human chromosomes 1q22, 16p11.2 and 11q13.2, respectively, are amplified in breast cancer [31]. The NSD3 gene on human chromosome 8p11.23 is amplified and overexpressed in a subset of breast cancer, lung cancer and pancreatic cancer [53]. By contrast, the NSD3 gene encodes full-length NSD3L and truncated NSD3S isoforms with or without SET domain, respectively, and lentiviral constructs of both isoforms are able to promote colony-forming potential of MCF10A cells [54], which suggests that the SET domain might be dispensable for the oncogenic potential of NSD3.…”

Integrative genomic and transcriptomic analysis for pinpointing recurrent alterations of plant homeodomain genes and their clinical significance in breast cancer

“…The PHD fingers in histone lysine methyltransferase WHSC1 (Wolf-Hirschhorn syndrome candidate 1) are critical for recruiting WHSC1 to oncogenic gene loci and driving multiple myeloma [15]. WHSC1L1, a homolog of WHSC1, is significantly amplified and overexpressed in a subset of breast, lung, and pancreatic cancers [16, 17]. Furthermore, the bromodomain PHD finger transcription factor (BPTF) is amplified and overexpressed in melanomas, and BPTF is required for c-MYC transcriptional activity and in vivo tumorigenesis [18].…”