Identification of TMEM115 as a tumor suppressor gene and clinical prognostic factor that influences TERT expression in pancreatic cancer

The catalytic component of telomerase, telomerase reverse transcriptase (TERT), is reactivated in immortalized cells and plays a crucial role in cancer development. Pancreatic cancer (PC) is frequently associated with loss of heterozygosity on the short arm of human chromosome 3. In a previous study, chromosome engineering experiments in PC suggested that putative tumor suppressor genes (TSGs) that act through TERT regulation are present on the 3p21.3 region. Here, we performed functional analysis using a human artificial chromosome (HAC) carrying only the 3p21.3 region (3p21.3-HAC) to directly clarify if TSGs are contained in the 3p21.3 region. We observed reduced TERT transcription following the introduction of 3p21.3-HAC into PC cells. Furthermore, to identify the specific TSGs functioning via TERT regulation in the 3p21.3 region, we performed RNA sequencing analysis using mouse Tert (mTert)-expressing murine LTPA PC cells containing either 3p21.3-HAC or the empty HAC vector. Through this analysis, we identified transmembrane protein 115 (TMEM115) as a novel TSG. Furthermore, both human TERT (hTERT) and mTert transcription can be suppressed by TMEM115. Thus, TMEM115 may contribute to PC development by functioning as a novel telomerase regulating factor via influencing TERT expression.