PT  - JOURNAL ARTICLE
AU  - Shakhawoat Hossain
AU  - Hiroaki Iwasa
AU  - Aradhan Sarkar
AU  - Junichi Maruyama
AU  - Kyoko Arimoto-Matsuzaki
AU  - Yutaka Hata
TI  - The RASSF6 tumor suppressor protein regulates apoptosis and the cell cycle progression <em>via</em> Retinoblastoma protein
AID  - 10.1101/334276
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 334276
4099  - http://biorxiv.org/content/early/2018/05/30/334276.short
4100  - http://biorxiv.org/content/early/2018/05/30/334276.full
AB  - RASSF6 is a member of the tumor suppressor Ras-association domain family (RASSF) proteins. RASSF6 is frequently suppressed in human cancers and its low expression is associated with poor prognosis. RASSF6 regulates cell cycle arrest and apoptosis and plays a tumor suppressor role. Mechanistically, RASSF6 blocks MDM2-mediated p53 degradation and enhances p53 expression. However, RASSF6 also induces cell cycle arrest and apoptosis in the p53-negative background, which implies that the tumor suppressor function of RASSF6 does not depend solely on p53. In this study, we have revealed that RASSF6 mediates cell cycle arrest and apoptosis via pRb. RASSF6 enhances the interaction between pRb and protein phosphatase. RASSF6 also enhances P16INK4A and P14ARF expression through suppressing BMI1. In this way, RASSF6 increases unphosphorylated pRb and augments the interaction between pRb and E2F1. Moreover, RASSF6 induces TP73-target genes via pRb and E2F1 in the p53-negative background. Finally, we confirmed that RASSF6 depletion induces polypoid cells in p53-negative HCT116 cells. In conclusion, RASSF6 behaves as a tumor suppressor in cancers with the loss-of-function of p53, and pRb is implicated in this function of RASSF6.