ASCC3 promotes chemosensitivity in colorectal cancer cells

The activating signal co-integrator 1 complex subunit 3 (ASCC3), a multifunctional protein, has been implicated as a prognostic marker in several types of cancer. However, mechanisms underlying its prognostic value are not fully understood. Here, we report that ASCC3 promotes sensitivity to chemotherapeutic drugs, such as 5-fluorouracil, cisplatin, and hydroxyurea, in colorectal cancer (CRC) cells, likely in a cancer type dependent manner. Increased chemoresistance resulting from ASCC3 loss is not due to reduced genomic instability as evidenced by enhanced accumulation of DNA damage and micronuclei following exposure to these drugs. RNA-seq analysis reveals that ASCC3 stimulates the expression of gene sets associated with mTORC1 signaling, glycolysis, and protein folding pathways in CRC cells. While promoting the serine biosynthesis pathway, we demonstrate, through extracellular flux assays and stable isotopes tracer analysis, that ASCC3 reprograms energy metabolism, favoring glycolysis over oxidative phosphorylation. Furthermore, we find that ASCC3 is required for PERK production upon ER stress. Impaired PERK production is associated with reduced levels of CHOP and caspase 3 following treatment with 5-fluorouracil, indicating that ASCC3 promotes PERK production to enhance cell death upon chemotherapy. Collectively, our work underscores molecular complexities underlying chemoresistance in the wake of ASCC3 loss in CRC cells.

激活信号共整合因子1复合物亚基3（activating signal co-integrator 1 complex subunit 3，ASCC3）是一种多功能蛋白，已被证实可作为多种癌症的预后标志物。然而，其发挥预后价值的分子机制尚未完全阐明。
本研究发现，结直肠癌（colorectal cancer，CRC）细胞中ASCC3可增强细胞对化疗药物（如5-氟尿嘧啶、顺铂及羟基脲）的敏感性，且该作用可能具有癌症类型依赖性。ASCC3缺失所导致的化疗耐药性增强，并非源于基因组不稳定性降低——这一点可通过细胞经上述药物处理后DNA损伤与微核的蓄积增加得以证实。
RNA测序（RNA-seq）分析显示，CRC细胞中ASCC3可激活与雷帕霉素靶蛋白复合物1（mTORC1）信号通路、糖酵解及蛋白质折叠通路相关的基因集表达。在促进丝氨酸生物合成通路的同时，本研究通过细胞外流量分析法与稳定同位素示踪分析证实，ASCC3可重编程能量代谢，使细胞更倾向于采用糖酵解而非氧化磷酸化供能。
此外，本研究发现，在内质网应激（ER stress）条件下，ASCC3是双链RNA依赖的蛋白激酶样内质网激酶（PERK）产生所必需的。经5-氟尿嘧啶处理后，PERK蛋白产生受损会伴随CCAAT/增强子结合蛋白同源蛋白（CHOP）与半胱天冬酶3（caspase 3）水平降低，这表明ASCC3可通过促进PERK蛋白产生，以增强化疗诱导的细胞死亡。
综上，本研究揭示了结直肠癌中ASCC3缺失所导致的化疗耐药性背后的分子复杂性。