Cancer is a heterogeneous disease driven by various genomic, epigenomic, and proteomic abnormalities. Though conceptually straightforward, targeting cancer-specific abnormalities proves practically challenging due to the complexity of the cellular functions of many potential cancer targets. Our lab is interested in unravelling the biology of cancer-relevant cellular proteins with poorly understood mechanisms. We strongly believe that this could lead to the development of novel therapies and the improvement of existing therapies. Currently we are focusing on two research areas in the context of breast cancer.
Profilin-1: an old protein with new functional twists
Profilin-1 (Pfn1) is a well-characterized actin-binding protein essential for cell proliferation, survival and migration, yet showing paradoxical antitumor and anti-metastatic effects in several types of cancer including breast. Our earlier work suggested a “spatial confinement” model to reconcile its opposing functions (Diamond et al., JBC, 2015). We proposed that Pfn1 has important yet poorly understood functions in the nucleus in addition to its well-characterized role as an actin-binding and regulatory factor in the cytoplasm. Our recent work (Zhu et al., Cell Rep, 2021) supports this model and reveals that nuclear Pfn1 physically interacts with the Super Elongation Complex (SEC) and functionally inhibits SEC-dependent transcriptional elongation of many pro-cancer genes including MYC. Furthermore, we offer clinical and experimental evidences that the anticancer activity of nuclear Pfn1 is decreased in a broad range of cancers by nuclear exclusion due to upregulation of its nuclear exporter exportin-6 (XPO6). Our more recent study (Zhu et al., Nat. Commun, 2022) further uncovered that nuclear Pfn1 plays context-dependent roles in DNA replication under normal versus stress conditions. Its effects on the reversal and resection of stressed replication forks have novel and important therapeutic implications for genotoxic chemotherapy efficacy of different cancers. Currently we are conducing more in-depth mechanistic investigation of nuclear Pfn1 in the context of DNA replication stress response and exploring new therapeutic approaches to target nuclear Pfn1 export to achieve tumor inhibition and chemo-sensitization. Our long-term goal is to continuously uncover novel "moonlighting' functions of nuclear Pfn1, connect such functions to the pathogeneses and therapies of cancer, and hopefully generate more paradigm-shifting evidence that essential proteins such as Pfn1 can be safely and effectively targeted in human diseases.
p97/VCP: a polyubiquitin-specific protein "segregase" orchestrating DNA damage response
Valosin-containing protein (VCP) is an evolutionarily conserved AAA+ ATPase involved in diverse cellular processes. Functioning as a “segregase”, VCP facilitates proteostasis by extracting polyubiquitinated proteins from various organelles and cellular structures for subsequent turnover. Studies in the last decade have solidified the essential role of VCP in chromatin-associated protein degradation and genome stability maintenance in the context of DNA damage response (DDR). However, due to the pleiotropic cellular effects of VCP , it had remained uncertain whether its DDR-related functions can be selectively regulated. Our recent work (Zhu et al., Cell Rep, 2020; Wang et al., Cancers, 2021) supported this theory and revealed that DNA damage-induced phosphorylation of VCP at Ser784 within its C-terminal tail specifically increases chromatin-associated protein degradation while having no effect on ER-associated degradation and cytosolic protein clearance. Our data suggested that pSer784-VCP is required for DNA damage repair, checkpoint signaling, and cellular survival in response to diverse genotoxic treatments. Importantly, we found that pSer784-VCP levels significantly correlate with poor survival outcome of chemotherapy-treated breast and pancreatic cancer patients. Therefore, pSer784-VCP is a clinically relevant DDR regulator with the potential of being both a chemotherapy predictive marker and sensitizing target.