Overexpression of LASS2/TMSG1 inhibited pHi recovery and significantly decreased MCF‐7/ADR cell migration due to the suppression of V‐ATPase function via LASS2/TMSG1 binding to subunit Voc.26 Furthermore, the downregulation of a positive regulator of V‐ATPase activity, TM9SF4, significantly inhibited tumor cell invasiveness and increased the cytotoxic effect of 5‐FU in colon cancer cells. The gene discussed is CERS2; the disease is colonic neoplasm.